Test 2 Flashcards
1
Q
Current amplitude 2
Membrane potential 2
A
absolute value
increases or decreases
hyperpolarizes or depolarizes
does not increase or decrease
2
Q
Most neurons
However, most neurons produce
Neurons are named for
A
receive synapses of/respond to many different neurotransmitters
only one neurotransmitter
the NT they produce
3
Q
Ionotropic ____ vs. Metabotropic____
A
(direct) ; ion channel
(indirect) ; intracellular signaling cascade
4
Q
What makes a neurotransmitter? 4
A
Located at the synapse - Mechanism of synthesis
Vesicular release -Mechanism of vesicle
loading/release
Produce a response - Mechanism of detection
Removed from the synapse- Mechanism of recycling
5
Q
Direct transmission
A
Release from a presynaptic
terminal directly onto a
postsynaptic terminal
6
Q
Glutamate
A
The major CNS excitatory neurotransmitter
7
Q
Glutamine/glutamate cycle 6
A
- Neurons turn glutamine into
glutamate via glutaminase
-note: glutamate is a charged
molecule - VGLUT (vesicular glutamate
transporter) pumps glutamate
into vesicles - SV releases glutamate into
synaptic cleft - EAAT (excitatory amino acid
transporter) pumps glutamate
out of synapse - Glia chemically change
glutamate back into glutamine
via glutamine synthetase - Glutamine transported out of
glia, into neurons via EAAT
8
Q
- VGLUT (vesicular glutamate
transporter) pumps glutamate
into vesicles 3
A
~SV has high [Cl]in (matches extracellular
space)
~v-ATPase uses energy from ATP to
pump H+ into SV
~VGLUT uses the electrochemical gradient of H+ and Cl- to power
pumping glutamate into the SV
9
Q
- EAAT (excitatory amino acid
transporter) pumps glutamate
out of synapse 2
A
~EAAT uses the electrochemical gradients for K+ and Na+ to power transport glutamate into the cell ~EAAT expressed in pre-, postsynaptic neurons, and GLIA (esp. astrocytes)
10
Q
NT Transporters 2
A
Each binding interaction changes protein
conformation, opens up other binding sites (NOT a pore)
Note: each step is reversible. Transporter can run in either direction, the direction is driven by concentration gradients
11
Q
GABA 2
A
The primary inhibitory
neurotransmitter of the CNS
Also, the major excitatory
neurotransmitter during neural
development
12
Q
GABA synthesis (2) and transport (1)
A
Synthesis enzyme: GAD, Glutamate decarboxylase
GABA is made from glutamate
Transporters: vGAT & GAT
(vesicular) GABA transporter
13
Q
GABA synthesis and transport cycle
A
glutamine → glutamate → GABA → into vesicle and released -> GAT reuptake → glutamate → glutamine
14
Q
Forebrain circuits are mostly
A
intermingled, interconnected
glutamate and GABA neurons
15
Q
Other NTs typically arise from 3
A
isolated lower nuclei
Lower nuclei are often intermingled/interconnected as well
Many of these non-GABA, non-glutamate axons connect very broadly across lots of neurons in the target circuitry
16
Q
Difference: the non-GABA, non-glutamate NTs arise
A
entirely from
these lower nuclei
17
Q
Upward Projecting Nuclei
GAD in situ hybridization (ISH)
Neurons producing GABA are
Choline acetyltransferase ISH
Neurons producing ACh
A
Some neurotransmitters are produced only by isolated clusters of neurons
everywhere
are only in the brainstem
18
Q
Acetylcholine (ACh) 2
A
The major excitatory
neurotransmitter in the
periphery, very different
role in CNS
Upward projecting brainstem nuclei: small groups of neurons send
axons upward that branch extensively throughout the forebrain
19
Q
Cholinergic inputs = Extreme version of
ACh modulates overall CNS activity: 3
A
divergence: small number of neurons
send branching axons throughout
forebrain
arousal, sleep, learning and memory
20
Q
Inputs by nature are
A
not specific; postsynaptic response depends on type of receptor expressed
21
Q
Diffuse projections
A
These projections are less specific/distinct tend to modulate entire circuits rather than individual neurons
22
Q
Volume transmission 3
A
Neuromodulation
Synaptic release… without a synapse
ACh extensively uses both direct and indirect transmission
23
Q
Biogenic Amines 4
A
~Highly restricted populations - only specific nuclei synthesize ~Very diffuse projections - send axons throughout the forebrain ~Almost entirely volume transmission - axon varicosities release transmitter out into extracellular fluid ~Almost entirely metabotropic signaling
24
Q
Dopamine (2 locations and purposes)
A
Substantia nigra → striatum
movement, cognition
VTA → Prefrontal cortex
reward, motivation
25
D1 and D2 - receptors in opposition? 3
2 types of metabotropic receptor
activate opposite signals
Outcome depends on the receptors a
postsynaptic cell expresses
Receptors can also interact and work
together, activate an entirely different type of
response
26
Parkinson’s Disease 2
First treatments: give dopamine precursors
[l-DOPA] → increase synthesis → increase release
But overloading the system with dopamine can cause problems as well
27
Norepinephrine 3
β2 receptors increase firing rate
⍺2 receptors hyperpolarize cells in a way that sharpens responses to big stimuli
Short-term increases attention, sensory responses, learning
28
Serotonin 3
Activates widely distributed
5-HT (metabotropic) and 5-HT3 (ionotropic) receptors
SSRIs (selective serotonin reuptake inhibitors) can treat mood and behavioral disorders by increasing duration of serotonin presence in extracellular fluid
Consequence of diffuse projections: side-effects of drugs can be wide-ranging, hard to control
29
Neuropeptides 3
1. Synthesis: genetically encoded expressed as a large precursor enzymatically cut to size
2. Transported to synapses, packaged in dense core vesicles
3. Released at synapses, but act via indirect volume transmission
30
POMC
One gene, encodes one big peptide,
| that can be cut into multiple different neuro-active peptides
31
Orexin/Hypocretin 3
Made in the hypothalamus
Two types of Orexin activate two types of Orexin receptor
Regulate arousal, appetite, narcolepsy, mood
32
Vasopressin and Oxytocin 3
Made in the paraventricular and other nuclei of hypothalamus
CNS and systemic effects
Modulates mood and social, sexual, and maternal behaviors
33
Ionotropic Receptors 5
An ionotropic receptor is, at its core, an ion channel…
each subunit has multiple transmembrane domains
The extracellular aspect contains
a ligand binding domain(s)
```
ATD =
N-terminal domain
Ligand binding domain
Transmembrane domain
Cut off here: C-terminal domain
```
Each receptor is made up of multiple subunits (homo or hetero)
34
3 Classes of Glutamate Receptors (4)
Named based on pharmacology
AMPA receptors:
Kainate receptors:
NMDA receptors:
35
Gene names:
GRI (Glutamate Receptor Ionotropic)_#
| Subunit names: Glu_#
36
AMPA Glutamate Receptors 2
permeability 3
Typically heterotetramers,
stoichiometry unclear
Ligand binding opens the
channel and…
Permeability:
CATION selective …
BOTH Na+ and K+
Ca2+ sometimes depends on subunits
37
AMPA receptor reversal potential 2
EAMPA is an average of the
reversal potentials of each
permeant ion, weighted by
its relative permeability
EAMPA = 0 mV
38
AMPAR single channel recording 2
Typically, AMPARs don’t exhibit 1
Quisqualate = agonist
Recordings made with agonist present, at different holding potentials (Vm)
voltage-dependent behavior
39
NMDA Receptors are
In order to activate, NMDA
receptors require binding of
both
but in the CNS there’s enough
Obligate heterotetramers:
Each channel must contain
2 GluN1 subunits and 2 non-GluN1 subunits
glutamate AND glycine
glycine floating around that it is just there and doesn’t matter, we’ll mostly ignore this
40
EGlutamate =
0 mV
41
NMDA Glutamate Receptors: Mg2+ block 4
At resting Vm, when the pore opens, it is quickly blocked by Mg2+ so no current can flow
at negative Vm, strong inward driving force
Mg2+ gets into the pore but can’t pass through
As Vm depolarizes, the Mg2+ driving force is decreased, block becomes less likely
42
NMDA current I/V curve 2
Nonlinear section: with each step more
channels are losing Mg block so current
can flow
Linear section: 100% of channels
are unblocked and active, amplitude
dictated entirely by driving force
43
NMDA Receptors: Coincidence Detectors 3
Simultaneously:
1. depolarize cell (remove Mg2+) & 2. synaptic release of glutamate
NMDARs specifically activate when
glutamate is present AND the neuron is
depolarizing, thus they sense when
synapses are activating together
Channel activates,
cations flow, Vm pulled toward EGlutamate
(0 mV)
44
NMDA Receptors: Coincidence Detectors 2 key points:
```
1. Coincidence detection means that
NMDARs activation reports something
specific to the neuron:
“The currently active synapses are
causing action potentials, these active
synapses are important”
```
2. Calcium permeability at those
coincidentally active synapses can serve
as a 2nd messenger, activate other
processes at those specific synapses
45
The Postsynaptic Density 2
The PSD is a complex array of interconnected proteins
Provides structure & support, and is an active part of synaptic and structural plasticity
46
An AMPAR in isolation is 2
non-functional
This protein alone wouldn’t even get
to the cell membrane
47
TARPs - 4
transmembrane AMPAR regulatory proteins
TARPs are auxiliary proteins Not part of the
channel itself, but vital for function
So, all AMPARs that have made it to the cytosolic membrane have TARPs integrated as part of the channel complex
AMPAR/TARP complex constructed in the ER. TARPs are necessary for AMPARs to exit into Golgi
48
AMPAR-TARP 2
This complex can at least get to the cytosolic membrane…
but what then?
on its own will just drift around
49
TARP interaction sites 3
PDZ-binding domain (links to PSD-95)
AMPAR/Non-phosphorylated TARP
diffuses around in membrane
AMPAR/Phosphorylated TARP
sticks to things
50
PSD-95 and family (PSD-MAGUKs) 1
PDZ domains bind: 4
Other domains 1
PSD-95 is an active, multi-purpose protein trap
PDZ domains bind: phospho-TARPs,
NMDARs, Ion channels, Transsynaptic adhesion proteins, etc
Other domains link PSD-95 to PSD structural proteins
51
PSD proteins like 3
provide
Homer, GKAP, and SHANK provide
the scaffolding to keep various signaling molecules in place and link to f-actin or other cytoskeleton
52
Synaptic Physiology 3
Receptors open, current flows
NT diffuses across the synapse,
binds receptors
Receptor Open
Probability
53
draw Synaptic Physiology curve
#13 slide 4
54
Why do receptors close? 2
```
1. Channel deactivation (channels
unbind from NT and NT is cleared from
synapse)
2. Channel desensitization (channels are
still bound to ligand, but close anyway)
```
55
Speed of deactivation and desensitization
| depend on
channel subunits AND interaction
| with other proteins
56
receptors open open probability 2
This is the
POSTSYNAPTIC CONDUCTANCE
aka gsynapse
This shape is a direct measure of
how channels open and close
57
Recording synapses: Excitatory Postsynaptic Currents (EPSCs)
| Excitatory Postsynaptic Potentials
EPSPs
I = V*gsynapse
V = I/gsynapse
58
Stimulating (evoked) eEPSCs 2
electrical stimulus - electric current applied
near axons evokes APs
optogenetics - presynaptic neurons express
light-activated channels
59
Non-stimulated EPSCs 2
(miniature) mEPSCs: non-action potential
mediated spontaneous release of presynaptic vesicles
(spontaneous) sEPSCs: synaptic release
caused by spontaneous action potential
firing + mEPSCs
60
Miniature EPSCs mEPSCs: 4
~caused by random (non-stimulated) activation of the vesicle
release process (e.g., random Ca channel opening, random
SNARE activation, etc.)
~confusing point: often referred to as spontaneous release, but
fundamentally different from spontaneous EPSCs
~by definition, NOT caused by action potentials, always recorded
with Na+ channels blocked
~evoked by a single vesicle (quanta)
61
Spontaneous EPSCs 3
~caused by random activation AND action potential induced
vesicle release
~confusing point: recordings of sEPSCs are mEPSCs PLUS
EPSCs caused by spontaneous action potentials fired by
presynaptic neurons
~recorded without blockers of Na+ channels
62
```
Rise time (kinetics, part 1)
Influenced by… 2
```
~subunit composition of receptors
~distance of synapse along dendrite, away
from recording electrode
63
Decay time (kinetics, part 2), often calculated as tau Influenced by… 6
~channel subunit composition
~channel deactivation
~channel desensitization
~pre- and post-synaptic structure
~neurotransmitter clearance from synaptic cleft
~distance of synapse from recording electrode
64
eEPSC amplitude, Presynaptic influences… 4
~number of axons stimulated: turn up your stimulus, more local axons will fire APs, bigger response
~vesicles/active zones/synaptic contacts per axon: if a single axon makes multiple contacts, bigger response
~probability of vesicle release at each synapse: more
vesicles released, bigger response
~possible, but not a major factor: quantity of
neurotransmitter in each vesicle
65
eEPSC amplitude, Postsynaptic influences… 3
~number of receptors at the synapses
~single channel conductance
~distance of synapse along dendrite away from
recording electrode
66
mEPSC parameters amplitude 4
Frequency
Influenced by… 3
Because mEPSCs are evoked by release of single vesicles the amplitude is dictated only by postsynaptic neuron
~number of receptors at the synapses
~single channel conductance
~distance of synapse from recording electrode
```
~number of synapses
~probability of release
~Often used as a way to
“count” relative numbers of
synapses across neurons
```
67
sEPSC parameters Amplitude 2
Frequency Influenced by… 4
Similar to mEPSCs except:
~Action potential evoked EPSC amplitude will depend on the number of
synapses between that particular axon and the postsynaptic neuron
```
~number of synapses
~probability of release
~amount of ongoing activity
in presynaptic neurons
~Often used as a way to
compare how active neural
circuits are at baseline
```
68
3 types of EPSCs: how to choose?
Record eEPSCs when you want: 3(last one has 2 sub ones)
Record mEPSCs when you want: 1
Record sEPSCs when you want: 1
~to test how strong specific input from a specific source is
~to get a bigger, more consistent response
~to stimulate the same set of synapses repeatedly
-measure changes to trains/bursts/patterned stimuli
-measure plasticity
~to measure how a neuron’s connectivity (number of synapses) might be changing
~to measure how activity of a neural circuit might be changing
69
How do we record NMDAR EPSCs? 2
To isolate AMPAR current: 1
To isolate NMDAR current:
block non-glutamate synapses
record at greatly depolarized Vm
block AMPARs
EPSCs are on the same time
scale, notice difference in kinetics
block non-glutamate synapses
record at resting Vm
(NMDARs blocked by Mg)
70
What can kinetics tell us? 4
NMDAR currents change kinetics
over development
Early developmental receptors
much more permeable to Ca2+
Longer lasting currents means
more longer integration time
This is because of a switch in subunits:
Young = GluN2B Older = GluN2A
71
Draw a neuron as an electrical circuit (basic)
look at thing
72
draw synapse as electrical circuit
look at thing #13
73
Membrane Nonlinearity: Esynapse 3
Eglutamate = 0 mV
EPSCs can sum linearly
Because bigger EPSPs are moving toward Esynapse: EPSPs sum nonlinearly, influencing ability to reach threshold
74
Membrane Nonlinearity #1: Esynapse (4 summary points)
As gsynapse increases, EPSCs can sum linearly
Because bigger EPSPs move Vm toward Esynapse:
EPSPs sum nonlinearly
Influences ability to reach threshold
Not time-dependent: depolarizations will always approach Esynapse asymptotically
75
Membrane Nonlinearity #2: VGCs 2
As the EPSP depolarizes the neuron, it can activate, and inactivate VGCs
VGCs can increase EPSP
amplitude, even when not firing an
action potential
76
Membrane Nonlinearity #2: VGSCs 4
The larger the EPSP, the greater nonlinear effect
Small increases in EPSP
amplitude can greatly increase
VGC activation
same time: EPSP X2
Supralinear summation
due to VCSC activation
second after first Summation is linear,
VGSC boost canceled out because VGSCs inactivated
77
VGSC: timing? 3
Activation happens faster than inactivation
Depolarization causes channels to activate, then inactivate
Timing between inputs can dictate supralinear or linear summation
78
Subthreshold depolarizations also activate
second stimuli after first
VGKCs
Sublinear summation
due to VGKC activation
79
Because EPSPs activate VGCs: EPSPs sum
also 2
nonlinearly
TIME-DEPENDENT: direction of
effect depends on input
synchronicity
```
Activation state of membrane
channels, and thus linear
EPSP summation, is in
constant flux because Vm
changes with every synaptic
input
```
80
draw effect of VGSC and VGKC on EPSP (including timing)
look at things
81
Membrane Nonlinearity #4: NMDARs 2
Increasing EPSP amplitude can activate NMDARs
Enhances amplitude and increases duration of EPSP
82
Membrane Nonlinearity #3: Capacitance 4 basics
Capacitance is a passive aspect of the membrane
The membrane is thin enough that charges interact across it via
electrical fields
```
The charge (Q) held is equal to the
capacitance (C) times the potential (V)
```
Every time Vm changes, charge flows
(current) on or off the capacitor
83
Membrane Nonlinearity #3:
Capacitance is a part
alters where
Capacitance is a part of the
electrical circuit of every neuron
Alters where the ions will actually
go once they enter the neuron
84
Membrane Nonlinearity #3: Capacitance steps 3
Synaptic conductance opens up, Na+ ions flow into the cell,depolarizes a patch of membrane: a local EPSP
These ions now diffuse (equally, randomly) in each direction
Some ions diffuse down the dendrite,
depolarizing it as they go, and the EPSP travels
85
Diffusing down the dendrite is easy:
But… as each new point along the membrane depolarizes, the capacitor
Thus, some current
ions are following their electrochemical gradient
draws charges
flows to the membrane rather than down the dendrite
86
As the EPSP recedes,
Capacitor discharges,
As those ions move, they don’t
Thus,
Vm returns to rest
ions flow off the membrane
necessarily move down the dendrite
some charges are lost to the EPSP
87
How does capacitance shape the EPSP? 2
Current is split going down dendrite and to
membrane capacitor = Rise is slower
As Vm repolarizes, current flows off capacitor Some add back to trailing end of the EPSP, some diffuse in other directions = Decay is extended
88
Membrane Nonlinearity #3: Capacitance, Functional consequence: 2
The more membrane an EPSP passes over,
the greater the effect of capacitance on
amplitude and kinetics
“DENDRITIC FILTERING”
By extending dendrites, neurons lose some
temporal information about their inputs
89
EPSP filtering = 2
(i.e., changing of amplitude and kinetics) occurs for the SAME REASON
that Vm doesn’t change instantaneously to a current step
Ions flowing into the capacitor are
delayed from contributing to Vm
90
DENDRITIC FILTERING
All neurons care about input timing, just on different scales
91
effects on EPSP summary
EPSP reversal potential: EPSP amplitude increases decrementally, asymptotically
VGCs can cause supra- or sub-linear EPSP summation
The more membrane an EPSP passes over, the more capacitance will decrease amplitude and slow kinetics
Bigger EPSPs will activate NMDA receptors, boosting amplitude
92
Not all dendrites are spiny: spiny 3
Aspiny
Cortical and hippocampal pyramidal neurons
Cerebellar Purkinje Cells
Striatal Medium Spiny Neurons
Cortical and hippocampal interneurons
Cerebellar Granule Cells
Many brainstem, spinal neurons
93
What is the purpose of the spine?
Think of spines as functional units: behave independently in the
processes of synaptic transmission and plasticity
94
Spine Structure 2
Mature spines have narrow necks, wide heads, at least one
postsynaptic density
Synapses on spines are almost always excitatory
95
Spines as compartments 4
To behave independently, a subcellular structure must isolate itself
1. Spines are electrical compartments
2. Spines are biochemical
compartments
The narrow neck of the spine serves to isolate the spine enough for it to behave independently
96
draw circuit diagram of spines
look at thing #15
97
Rh =
Rn =
Ra =
resistance of the membrane of
the spine head (cytosolic membrane)
axial resistance of the spine neck
axial resistance of the dendrite
98
Rn is inversely related to
As the neck gets narrower,
equation
the square of the radius
resistance goes up exponentially
R = p(L/A)
99
EPSP Amplification Within Spines
Larger local depolarization means
more activation of: 2
Higher Rn is means that spines will
depolarize more relative to dendrite
for a given gsynapse/EPSC
1. Voltage gated channels
2. NMDA receptors
100
EPSPs are amplified by spine-localized Na+ channels
Stimulate single spines with
glutamate uncaging
Record EPSP at soma
block Na with TTX = decrease EPSP from synapses
101
Amplification is 6
voltage dependent
EPSP amplitudes are reduced by TTX
EPSC amplitudes are not
Depolarization is required for amplification
EPSPs evoked on dendrite shafts are
not amplified
Suggests that voltage-gated channels
are actually in the spines
102
Action Potentials Depolarize Spines 3
Action potentials activate local ion channels, Ca influx within spines
Action potentials evoked in the soma depolarize dendrites, lead to Ca influx in dendrites and spines
Influx too fast to be diffusion of Ca into spine from dendritic shaft
103
Backpropagating Action Potentials 2
APs are initiated in the AIS, travel down the axon
Local depolarization at AIS actually travels in both directions, through soma and out dendrites
104
Action potential depolarizes spine, calcium comes in =
Voltage-gated Ca channels must be present in spine membrane
105
Electrical Signals at Branch Points 5
Rn is much higher than Ra (axial resistance of the dendrite)
Signals moving from LOW (dendrite) to HIGH (spine) R do so very efficiently
Thus, spine Vm closely matches dendrite Vm
Signals moving from HIGH (spine) to LOW (dendrite) resistance do so inefficiently
Thus, spine Vm can lose amplitude
when it becomes dendrite Vm
106
NMDA receptor activation within spines how? 3
NMDAR Mg block is alleviated near AP threshold
Thus, we typically think of
NMDARs activating only to big,
suprathreshold events (i.e., APs)
But… what if spines are independently depolarizing more to small
inputs than the rest of the dendrite and cell body?
107
NMDA receptor activation within spines SUBTHRESHOLD input trains 4
(evoke no action potentials)
activate NMDA receptors
within spines
Stimulus train evokes small EPSCs
Initiates calcium influx
Larger depolarizations, and Ca
signaling, can be present even
for moderate synaptic inputs
108
Spine shape
Longer spine necks
There are physical limits on
modulates responses
meaning less efficient transfer of EPSPs from spine to dendrite
spine size/shape for synaptic signals to escape
109
Spine EPSPs sum
Synchronous EPSPs from different spines sum
Dendrite shaft synapses sum
linearly, dendrites do not
linearly
sublinearly
110
Synchronous EPSPs from different spines sum linearly: 4
(1) because of high Rn,
(2) spine EPSPs are larger within the spine, so
(3) amplitude is boosted by VGCs/NMDARs,
(4) enough to overcome the sublinear effects on summation
111
Summary: Spines as Electrical Compartments 3 (final one includes 3 subpoints)
Spine geometry (especially neck length and diameter) dictates electrical properties
High Rn allows spines to amplify EPSPs locally
Bigger local EPSPs:
~activate NMDA receptors
~activate voltage gated channels
~sum linearly instead of sublinearly
112
How do you make a biochemical compartment? 1
Biochemical signals propagate because proteins: 3
Biochemical signals shut off because: 2
Cell can’t seal off a section, can only constrict an area to limit diffusion
are linked in a complex (local)
are held in close proximity (local)
diffuse (local and distant)
signal’s enzymatic activity deactivates it (e.g., GTP-ase)
signal removed from system (e.g., calcium pumped out) signal reverts to inactive state over time
113
Spines are Unique Structures 3
Dendrite cytoskeleton is based on microtubules (tubulin)
Spine structure is based on microfilaments (actin)
Size and shape are highly flexible/dynamic
114
Spines contain
so
thus 2
entire signaling pathways
Receptors, second messengers, effectors,
substrates are all within the spine
Signal does not need to travel in and out of the spine
Effects are local, contained, synapse specific
115
Ca Signaling in Spines (1 + 2 sub)
Calcium comes in via
Narrow neck is
```
Influx into small volume enhances
local concentration changes:
~nano- or micro-domain around
channel(s) itself
~smaller “bulk” change within entire
spine
```
NMDARs, VGCs, can also be released from
intra-spine ER
restrictive to diffusion (calcium escape), keeps signal local
116
Signaling Cascades in Spines summary
Narrow neck is restrictive to diffusion of enzymes
When substrates are concentrated locally, enzymes act quickly and signal shuts down before it travels out of spine
When substrates are not local, signal spreads beyond the spine
Allows synapse specificity. This compartmentalization allows spines to behave independently, reacting only their own synapses
117
Different Signals Spread Differently 4
Diffusion is efficient over short
distances, inefficient over long
Spine volume, neck width and length
restrict diffusion
The major factor in signal spread is
duration of activation
Signal spread altered by other factors: membrane association of
signal or substrate molecule, diffusion by upstream/downstream
factors, positive feedback/regeneration of the signal
118
Different Signals Spread Differently simply put 2
Simply put:
Quick-acting signals stay local
Long-lasting signals overcome
restricted diffusion, spread
farther
119
Spine abnormalities relate to
disease
120
Spine abnormalities in neurodevelopmental
| disorders
Mixed changes in spine number and morphology
121
Spine abnormalities also in
schizophrenia, Alzheimer’s disease
122
Most synapses aren’t
Synaptic signals (EPSPs) must travel along
Signals may
How depends on
on the cell body
dendrites to the cell body
interact within a dendrite branch
EPSPs interact and affect the cell
depends on the properties of the dendrites
123
Passive Dendrites 3
True passive dendrites are those without
voltage-activated channels
(they may still have ion channels, but those ion channels aren’t opening or closing)
Truly passive dendrites aren’t really very
common in the CNS (or nearly as interesting), but they’re a good place to start
124
EPSP amplitude decreases with
distance
125
Decremental Propagation Forces opposing the EPSP 3
Ra = axial resistance of the dendrite
1/Rm = resistance (conductance) of the membrane
Cm = capacitance of the membrane
126
Dendrite axial resistance 4
Ra = axial resistance of the dendrite
(low compared to Rm) just like Rn (resistance of the spine neck)
R = p(L/A)
bigger dendrites have less resistance,
less EPSP attenuation
synapses farther out pass through more
resistance, have more EPSP attenuation
127
Cm = capacitance of the membrane 3
C = e(A/d)
A is the surface area; longer dendrites have more membrane, have more capacitance
the farther a synapse is out on the dendrites, the more Cm will alter EPSP shape
128
Rm = resistance of the membrane 3
(high relative to Ra)
signal amplitude will decrease whenever ions flow across the membrane rather than down the dendrite
the lipid bilayer itself has a very high resistance, so by itself is very good at allowing electrical signals to propagate
129
But… Rm also includes the sum 2
of every open channel in the membrane
(This is why I hedged earlier and said 1/Rm)
At rest, the membrane has some permeability, especially to K+, so there are always ion-permeable channels open throughout the membrane
130
Leak Channels 5
2-pore-domain K+ channels (aka 2-pore K+ channels, or K2p)
Does not mean that the channel has 2
pores!
It means that each subunit has two domains that become part of the pore
2 subunits form a dimer, making a complete channel
Voltage-INDEPENDENT channels: = most responsible for resting pK, which largely controls Vm and Rm
131
Recording leak channels 2
Physiology is straight forward (voltage steps match current steps)
```
Because channels aren’t doing
anything: channels are already
open, give square, evenly
spaced (linear) currents in
response to voltage steps
(just following Ohm’s law)
```
132
Decremental Propagation As an EPSP passes by any open K+ channel: 3
Vm shifts away from EK
UK increases, more ion flows out those
open channels
This outward current flow decreases EPSP
amplitude
133
Input Resistance 3
Input resistance (aka: Ri or Rinput) is the total resistance that a current encounters when it enters a cellular compartment
Ri thus dictates the amplitude of the change in Vm
In a big spherical neuron, Ri would be equivalent to Rm, but when a spine or dendrite is electrically isolated, it has its own unique Ri and will behave independently
134
Input Resistance steps 2
1. Channels open, ions flow in, channels
close. This moving clump of ions is the
EPSC. Their presence depolarizes the
membrane, the EPSP.
-They now have to go somewhere
(making the EPSP propagate). The
combined resistance to their movement
is Rinput which at this point is mostly Rn
```
2. Ions flow down the dendrite, the
major resistor is now Ra
-At this point, receptors are closed,
meaning gsynapse is no longer
contributing to Rinput
```
135
gsynapse is
Does gsynapse change membrane time
constant (tau=RC)?
Shouldn’t a bigger gsynapse actually
cause a smaller EPSP?
small relative to the overall
membrane resistance Rm
Typically, not enough to matter
(there are always exceptions),
because gsynapse is so small
ions travel away
from the synapse
(where those channels have
now closed)= EPSP = V = I/Rinput
136
Dendrite electrotonic length
EPSP travels
(Electrotonic) Length Constant
in both directions and gets smaller as it goes
137
Length Constant
neglect
lengthConstant = (Rm/Ra)^1/2
Ro = resistance outside ≈ 0
138
Skinnier dendrite 2
More dendrite ion channels 3
More attenuation and Shorter length constant
Lower Rm = Shorter length constant and
More attenuation
139
By considering length constant
instead of dendrite
length,
we get a
better idea of how
EPSPs will propagate
140
Length constant: physiological meaning When we measure: 2
we can infer things
which then helps us understand the
relative impact of synapses on
* long LC means distal EPSPs
* short LC means distal EPSPs
* dendrite size
* dendrite ion channels
about that cell type’s dendrite
length constant,
proximal vs. distal dendrites
will stay large
will be small
141
Active Dendrites 2
Dendrites actively respond to their inputs to shape them
voltage-gated channels + all of the channels we will discuss can be activated/modulated by signaling pathways
142
What do active dendrites do? 4
Amplify or suppress EPSPs
Equalize inputs (so distal
and proximal synapses can
have similar impact)
```
Back-propagate somatic
action potentials (bAPs)
```
Initiate/propagate dendritic
action/plateau potentials
143
Dendrites Express Sodium Channels 2
“persistant” Na+ channels (INaP) and “normal” Na+ channels
144
Dendritic VGSCs
APs are evoked by in___; Dendrite VCSCs are required for__
Dendrite VGSCs: important for both
back-propagate APs
AIS; bAPs
subthreshold and suprathreshold events
145
draw bAP
look at thing #17
146
Dendrite VGKCs are
Dendrites have a 3
Component 1 stronger
different from somatic
2-component K+ current
1: fast and inactivating
2: slow and sustained
farther out in dendrites
147
Dendrite K-conductances have
Thus,
Dendrite VGKCs: important for both
large initial activation, which then inactivates more than it does at the cell body
the effect of VGKCs on suppressing EPSPs more transient farther out in the dendrites
subthreshold and suprathreshold events
148
Ca channels in dendrites study how?
(Barium sometimes used to study Ca
| channels: Ba does not activate secondary processes that alter channel gating)
149
(Ca stuff)
Single EPSPs are
EPSP trains activate
bAPs activate
Ca channels are
amplified by Ca channels
dendritic Ca influx (non-NMDAR-mediated)
dendrite Ca channels
activated by (and thus: amplify) subthreshold and suprathreshold signals
150
Calcium Action Potentials in Dendrites
Some neurons exhibit voltage-dependent Ca2+ channel mediated action potentials
151
Strong repeated synaptic stimulation can lead to both
```
simple spikes (standard Na-mediated) and
COMPLEX SPIKES (Ca and Na spikes mixed)
```
152
Na spikes originate in
Ca spikes originate in the
the axon initial segment
dendrites (very little VGCC expression in axon or soma)
153
HCN Channels in Dendrites
HCN channels are activated by 2 main things:
HCN currents are often
called
HCN channels have a cyclic nucleotide binding domain
1: cAMP (often via metabotropic signaling)
2: hyperpolarization
Ih for hyperpolarization-activated
154
HCN currents provide a mechanism to: 2
difference between activators
- modulate EPSPs
- control excitability via metabotropic receptors
Hyperpolarization is used in lab to study these channels, but cAMP is more physiological mechanism of activation
155
HCN channels are permeable to
Reversal potential is
HCN1 channel expression
HCN-/- neurons are
K+ and Na+ (and maybe Ca2+)
Eh ≅ -20 to -30 mV
increases as you go out the dendrites
hyperexcitable
156
What happens to Vm when an HCN channel activates?
which causes
Overall, HCN channels
Neuron depolarizes
HCN channels suppress EPSPs
decrease excitability
DESPITE being depolarizing
157
Excitability is a balance
which
between Vm and Rm
can be controlled locally
158
If Vm and Rm are uniform across the neuron
If HCN channels are active in an area of dendrite
EPSP propagates normally, amplitude
decreases exponentially with length constant
As EPSP propagates through this local region: EPSP “amplitude” is depolarized …BUT… EPSP amplitude decreases more rapidly in this area
159
HCN channels depolarize, but suppress activity 3
Provide mechanism for metabotropic modulation of EPSPs
Local changes to both Vm and Rm alter propagation of EPSPs as they pass through
EPSP propagation and cell
excitability are a tug-of-war
between Vm and Rm
160
NMDA Channels in Dendrites
Test with
EPSPs reaching a certain amplitude will activate, and be amplified by, NMDA receptors
NMDAR antagonist, or by hyperpolarizing cell so Vm doesn’t reach NMDAR activation range
161
NMDA Spikes in Dendrites 3
Very small, distal dendrites may
not have many ion channels
```
Large EPSPs (due to very high
Rinput) activate NMDA receptors
```
Can induce a lasting depolarization
that propagates and regenerates
(as it passes synapses where
glutamate is present)
162
Plateau Potentials
NMDA spike vs Plateau Potentials
therefore
Sustained dendritic depolarization lasting beyond the end of the synaptic input
NMDA spike is an amplified EPSP
Plateau potential extends in duration
beyond the EPSP
```
Plateau potential depends
on NMDARs, but is further
amplified and extended by
voltage-gated Na and Ca
channels
```
163
Spiny dendrites have 1
Extra-synaptic receptors 2
Trains of input cause 1
greater surface area, more nonsynaptic (or extrasynaptic) NMDARs
- Receptors not linked to a scaffolding protein (e.g., PSD-95) will be diffusing freely around the membrane
- Most neurons have lots of these extra-synaptic receptors
glutamate spillover from synapses,
activating non-synaptic NMDARs, inducing plateau potentials
164
Physiological meaning of plateau potentials 3
Plateau is a depolarization long past EPSP duration
Inputs arriving later (asynchronous) have a greater impact if dendrite is in a plateau
Fundamental shift in temporal integration
165
Plateau Potentials 3 process
Trains of high frequency input
cause glutamate to build up in
synapses faster than it can be
removed
Glutamate then diffuses out of the
synapse (“spillover”) where it can
bind any receptor is runs into until
it runs into a transporter
A rush of glutamate spillover can activate non-synaptic AMPARs and NMDARs, causing a large segment of dendrite to exhibit sustained depolarization: plateau potentials
166
So what is the true Rm?
because
In constant flux and dependent on local conditions: diameter, synapses firing, channels activating/ deactivating/inactivating
Ra and Rhcn both changing with distance down the dendrite
167
Dendrite-restricted signals 3
NMDAR spikes tend to be restricted to the
distal synapses
Alter local integration within branches, or among close branches
While a single NMDAR spike might not
propagate all the way to the soma, it can amplify a cluster of synapses enough that EPSPs from tiny distal dendrites do get to the soma
168
Dendritic non-linear events 3
result
Back-propagating APs
NMDAR spikes
Plateau potentials
Unique to the physiology of dendrites, major impact on synaptic integration and plasticity
169
Testing presynaptic physiology
requires
Record postsynaptic response with electrode and stimulate axons
Optogenetic activation
Dual recording
recording postsynaptic responses
Easiest, but…lacks control over exactly which axons you are stimulating
Better control over cell subtypes you are stimulating, but…still usually lacks control over number of cells activated
Most control over cell you are stimulating, but… hardest to do
170
Autapses: 2
in sparse cell culture, cells synapse onto themselves
Not very physiological, but super useful for molecular dissection of presynaptic machinery
171
What postsynaptic measures tell us about presynaptic release 3
Variability: how many vesicles tend
to be released?
Failure rate: how often is there no release at all?
Measure how a protein/mutation alters
vesicle release
172
But… synapses don’t activate
have
just once
Short-term plasticity (STP)
173
Short-term plasticity (STP) 5
Synaptic strength changes bidirectionally and continuously in response to the frequency of activity
STP is an ongoing type of plasticity
Time course is typically less than 500 ms
Gives neurons a “memory” of that period
of activity, but isn’t saved long term
Most often we study presynaptic STP
174
When an action potential depolarizes a presynaptic terminal, how likely
is it that a vesicle will be released?
Probability of release (Pr)
175
Low Pr synapse
High Pr synapse
Tend to have smaller readily releasable pool
Tend to have larger readily releasable pool (more vesicles docked and primed)
176
Short-term Synaptic Facilitation 3
Low Pr synapse
Repeated presynaptic action potentials
EPSC amplitude increases (facilitates) across the stimulus train
177
STP and Neural Coding 3
Inputs to pyramidal neurons tend to come in bursts
Amplitude increasing due to
increasing EPSC/Temporally summing
EPSPs
Spiking becomes more
probable later in burst
178
STF mechanism 3
Presynaptic Calcium Buildup
Second input comes before calcium is completely removed from presynaptic terminal, so it builds up
Calcium increases more, more vesicles release more transmitter
179
Short-term Synaptic Depression 3
Low Pr synapse
Repeated presynaptic action potentials
EPSC amplitude decreases (depresses) across the stimulus train
180
STD mechanism?
Diminished Readily Releasable Vesicle Pool
More of the docked and primed vesicles are released to first input
Readily releasable pool of vesicles is smaller for subsequent inputs, less transmitter released
181
Short-term Synaptic Depression 2
EPSC amplitude decreases
(depresses) across the
stimulus train
Spiking more probable at the
beginning of the burs
182
Paired Pulse Ratio 3
stimulate two APs vary interval between
(ISI: inter-spike or inter-stimulus interval)
Record postsynaptic response
PPR (EPSC2/EPSC1)
183
Asynchronous Synaptic Vesicle Release 3
Big single stimulus, big immediate response… (Synchronous release)
and then lots of small, late responses
(Asynchronous release)
With trains of stimuli, big responses break
down over time
184
Asynchronous Release Physiological Function 2
In vivo, most synapses are active steadily or in bursts/ action potential activity is always ongoing
Asynchronous release can provide a tonic signal whose strength is modulated more by
action potential frequency than by single spikes
185
Mechanisms for Asynchronous Release
+3 ex
Asynchronous release is Ca2+-dependent, but in a different way, the mechanisms are unclear
Different calcium source
Different calcium sensors
Different vesicle pools
186
presynaptic physiology Summary
Presynaptic physiology assessed by measuring postsynaptic responses
Changes to presynaptic function will result in altered probability of release (Pr)
Low Pr synapses show paired pulse facilitation, because calcium builds up in terminals during bursts
High Pr synapses show paired pulse depression, because readily-releasable vesicles are released during the first event, leaving fewer vesicles for later events
187
Ionotropic GABA receptors (GABAARs) 4
Different genes encode different subunit
Each subunit has 4 transmembrane domains
Both N- and C-terminal domains are extracellular
Intracellular domains are in “loops” between TM domain
188
Ionotropic GABA receptors (GABAARs) Anion Permeability 2
Positively charged AAs in and
near the M2 transmembrane
segment help make the
selectivity filter
Channel is permeable to Cland to a lesser extent
bicarbonate (HCO3-)
189
Ionotropic GABA receptors (GABAARs) structure type4
The receptor is an obligate hetero-pentamer
Most typically made of 2 ⍺, 2 β, 1 gamma
Subunit mix is vital, and interesting for GABAARs: (not unique to GABAARs necessarily, just a good case study
GABA & other ligand binding sites are at the interface between subunits, specific arrangement of subunits requird
190
GABA Systems as Drug Targets
Barbiturates: allosteric modulators, enhance GABA binding; agonists
Ethanol: allosteric modulator, increases channel open probability
Benzodiazepine: allosteric modulators, increase single channel
conductance
191
Does activating GABA increase inhibition?
Effects are complicated: excitatory and inhibitory neurons are inhibited by inhibitory synapses
192
Sources of Inhibition 4
Different neuron types use
GABA as a neurotransmitter
GABAergic cell types are
distinct in morphology,
biochemistry, and
electrophysiology
GABAergic cell types
synapse on different parts of
postsynaptic cells
GABAergic projection
neurons are a major output
of many circuits (including
cortex and hippocampus)
193
Locations of Inhibitory Synapses 2
The location of inhibitory synapses can dictate how they modulate activity
Different inhibitory cell types send axons to distinct regions of postsynaptic cells
194
Feed-forward/-back Inhibition 4
Both inputs to and outputs from a GABAergic neuron define how it interacts w/n a circuit
Feedforward tends to modulate the onset and timing of a response
Feedback tends to modulate the duration of a response
Most CNS circuits have both
195
Location of Inhibitory Synapses 2
Most inhibitory synapses are on dendritic shafts
Rare inhibitory synapses occur on spine necks or heads
196
Molecular Structure of Inhibitory Synapses 2
Inhibitory synapses are
structurally distinct from
excitatory, but are built on
similar principles
GEPHRYN serves as the scaffold that links receptors,
transsynaptic proteins, and signaling molecules to the
cytoskeleton
(analogous to PSD-95)
197
GABAARs are
IPSC kinetics are
```
Synaptic conductance (IPSG)
amplitude is equal to:
```
Cl- permeable channels, so these inputs
typically reverse at Ecl
dictated by the opening and closing of channels at the synapse
single channel conductance multiplied by number of open channels
198
Recording IPSC/Ps is often done by
Or, hold Vm depolarized (= -30 or 0 mV), and use
increasing driving force and Recordings meant to isolate IPSCs often use artificially
high [Cl]in to make events larger
physiological [Cl]in, but this requires blocking VGCs
199
IPSP Direction/Amplitude Depends on
Depending on age, cell type, activity levels, etc
In adult pyramidal neurons,
ECl
ECl (EGABA) can range from -30 mV to -75
it is typically toward the hyperpolarizing
end of the range
200
Chloride Transporters
change from NKCC1:
Na+, K+, Cl- Cotransporter 1 to
KCC2:
K+, Cl- Cotransporter 2
over development
201
What happens when ECl is
| hyperpolarized to Vm? 4
1. Channels open
2. Cl- negative ions enter (outward current)
3. Vm hyperpolarizes locally
4. IPSP propagates down dendrite
202
(ECl is hyperpolarized to Vm?) IPSPs are subject to the same decremental propagation (dendritic filtering) as EPSPs: 3
and
~capacitance
~membrane and axial resistance
~active membrane properties
Length constant applies to IPSP
decremental propagation, same
as for EPSPs
203
(ECl is hyperpolarized to Vm?) IPSPs sum, 1
why? 3
nonlinearly
-----
IPSP amplitude asymptotically approaches Egaba
Hyperpolarizing IPSPs activate fewer VGCs (IPSPs might change steady-state
inactivation, but aren’t activating
these channels)
Different recording conditions give different HCN activation curves
(hard to tell if HCN channels will matter to IPSPs)
204
(ECl is hyperpolarized to Vm?) HCN channels regulate IPSPs
Faster kinetics, slight rebound
depolarization after IPSP due
to HCN channel activation
Major effect on IPSPs
comes from HCN channels
that are already open
However…Modeling studies suggest
that even small IPSPs
activate additional HCN
channels
205
What happens when Vm = ECl? 3
1. Channels open…
2. Cl- diffuses back
and forth equally
3. No net charge
flow, no change in
Vm, no IPSP
206
Vm = ECl? IPSG Changes 4
Rm
Regardless of whether ions flow/Vm changes, opening these channels changes Rm
While Rm is decreased, passing EPSPs
will have be reduced in amplitude
As EPSPs propagate past the now-open GABAAR channels, there will be a greater loss of ions, decreasing EPSP amplitud
207
Vm = ECl? Shunting Inhibition 4
the decrease in EPSP from opened GABAR
Shunting inhibition is local,
conductances don’t propagate
When ions diffuse, current flows.
Where current flows, Vm changes.
E/IPSPs propagate when ions move.
With shunting inhibition: Rm changes, but ions don’t move. So this signal does not propagate
208
Shunting inhibition is local so 2
Only signals that pass along
the dendrite with the shunting
synapse will be inhibited by it
This inhibition is specific to
the dendrite branches with
activated GABAergic
synapses
209
What happens when ECl is
| depolarized to Vm? 4
1. Channels open
2. Cl- negative ions leave the cell (inward current)
3. Vm depolarizes
4. Cl- ions diffuse to fill local area of lowered [Cl-] depolarizing IPSP propagates down dendrite
210
What does a depolarizing I*PSP do? 3
1. dIPSPs can be excitatory
2. dIPSPs can inhibitory
3. dIPSPs can be both
211
dIPSPs can be excitatory 3
Giant Depolarizing Potentials (GDPs)
Earliest circuit activity in cortex are
GABA-mediated GDPs
Evokes AP bursts
212
dIPSPs can be inhibitory 3
dIPSPs shunt via gsynapse
dIPSPs activate VGKCs
dIPSPs inactivate VGSCs
213
dIPSPs can be both 2
Current clamp stimuli and Add GABA
AP inhibited THEN APs evoked
214
draw dIPSPs can be both conducatnce and IPSP curve
look at thing #21
215
What is excitatory? What is inhibitory?
Rather than thinking about
de- vs. hyper-polarizing think:
does the input change
probability of an AP, pspike?
216
Dendritic Inhibition 2
GABAergic cells that target
dendrites: inhibits dendritic
Ca spikes and plateaus
```
GABAergic cells that
target the cell body
don’t inhibit dendritic
Ca spikes or plateau
potentials
```
217
Somatic Inhibition
Activating GABAergic cells that target the cell body inhibits Na+ spike outputs
218
Inhibition of Inhibition
GABAergic neurons receive inhibitory
input from other GABAergic neurons
Specific cell subtypes DISINHIBIT neural
circuits
219
Summation
Synaptic potentials add or subtract to each other,
depending on type, timing, location of inputs, and
membrane properties
220
Spatial summation 3
Dendritic branches: summation within
branches; PSPs interact
Soma: summation across dendrites
Axon initial segment: where summed PSPs
become APs
221
Synaptic Integration 3
+1
Temporal Integration
E/I Integration
Spatial Integration
Keep in mind that while we discuss these modes of integration
individually, a real neuron is performing these three types of integration
simultaneously and continuously
222
Often, the most important aspect of integration is 2
interaction between mechanisms:
one mechanism amplifies EPSP enough to activate further amplification or to offset suppression
223
Inputs sum differently
Increasing the number of local synapses activated causes
across dendrites
supralinear EPSP summation
224
Supralinearity is
It takes
enhanced farther out dendrites (increasing gain)
| fewer inputs to
achieve supralinearity
farther out dendrites
decreasing offset
225
NMDARs
NMDA receptors are
Na+ and Ca2+ channels
amplify distal inputs
necessary for supralinearity in distal dendrites
also boost the initial NMDAR amplification
226
Temporal summation is
Temporal summation occurs
Proximal dendrites
enhanced in distal dendrites
across a broader time window in distal dendrites (EPSPs sum together even when stimulus interval increases, i.e., inputs don’t need to be quite as synchronous)
require better synchrony for summation
227
Temporal and spatial
| summation
interact
228
Neural coding strategy
Distal synapses can
shifts for different synapses
| drive spiking MORE effectively
than proximal synapses
enhanced local spatial and temporal summation
229
Summary: Integration within dendritic branches 2
Synaptic integration along a dendrite is not uniform: local spatial integration and temporal summation change with
distance along dendrite
Coding strategy changes depending on dendrite location: temporal synchrony important close to the cell body, greater
summation occurs in distal dendrites
230
How do neurons integrate different dendrite
| branches? 2 models
Global integration model:
Synapses are independent
Inputs sum together at AIS
(spoiler: it doesn’t work this way)
```
Multi-stage integration model:
Local synapses interaction within
each branch
Within and between branch
interactions are different, both matter
```
231
Individual branch spikes
Local synaptic integration within distal dendrites
Without further input,
Proximal dendrites
Without further input,
often don’t propagate
may evoke local spikes
propagated EPSP is too small to evoke APs
don’t tend to exhibit local spikes
propagated EPSP is too small to evoke APs
232
Inputs across branches
Multi-branch depolarization
allows
Branches can
sum supralinearly
propagation of dendritic spikes that otherwise fail
behave and sum as units, then can work together to evoke activity
233
The “job”* of inhibition is to
make it
harder for the neuron to reach AP
threshold
234
There are 3 major ways GABAergic inputs
| inhibit excitability:
1. Move Vm farther from threshold
2. Decrease Rm
3. Decrease temporal summation
235
Inhibition changes
Gsynapse -
HCN conductance
both Rm and Vm
change in Rm dictated by
channels opening and closing
activated by the
IPSP change Rm, timing dictated by channels opening and closing
236
IPSP (w/ VGCs) -
Expected IPSP (no VGCs) -
change in Vm caused
by current flow, timing dictated by
Gsynapse, membrane dynamics, and VGCs
```
change in Vm caused
by current flow, timing dictated by Gsynapse and
membrane dynamics (Ra, Rm, and Cm)
```
237
IPSPs take Vm
IPSP - change in Vm caused by
Hyperpolarization means
farther from threshold
current flow, timing dictated by IPSC,
membrane dynamics, and VGCs
you have farther to go to get to threshold
More excitatory current needed to get there (Ohm’s Law)
238
Any opening channel
Conductances
Any change in Rm makes it
decreases Rm
sum together
harder to change Vm More excitatory current required (Ohm’s Law)
239
Gsynapse makes Vm
harder to move
240
IPSGs change 2
EPSP kinetics
tau is smaller (faster), EPSP kinetics are faster during IPSPs
241
IPSGs change
Changes in kinetics alone
To reach threshold during inhibition: 2
EPSP temporal summation
can decrease summation
bigger EPSPs
or
higher input frequency (i.e., shorter interval )
242
Inhibition does all of these things, together 4
1. GABAARs shunt excitation by decreasing
Rm
2. Hyperpolarizing inhibition shifts Vm away
from threshold
3. Inhibitory conductances speed up the membrane time constant, decreasing
temporal summation
4. In some cells IPSPs can activate HCN channels to further decrease Rm (but this also makes IPSPs shorter in duration)
243
Each Neurotransmitter has
Metabotropic Receptors (m-Rs)
244
Each neurotransmitter has multiple types of m-R, which
On a single neuron, different m-Rs for the same neurotransmitter can
m-Rs can effect both
With m-R signaling, effects are
sometimes do opposite things for a cell
activate different pathways
pre- and post-synaptic physiology
(sometimes in opposite directions)
complex, we can’t just think of a neurotransmitter as being excitatory or inhibitory
245
mGluRs 2
Glutamate
Mostly homodimers, but some heterodimers as well
246
GABABRs 3
Different isoforms are
A functional receptor is an obligate heterodimer of:
1x GABAB1
1x GABAB2
produced via alternative promoter usage, resulting in different transcription of the same gene: GABAB1a GABAB1b
247
GABAB(1a,2) and GABAB(1b,2) receptors
activate different things
248
m-Rs are GPCRs 3
VFD - Venus Fly Trap
domain binds to ligand,
which changes protein
conformation
Seven transmembrane
domains (7TM receptors)
Intracellular loops bind to
the alpha subunit of a Gprotein
249
G-proteins have
subunits
multiple active components
alpha and beta-gamma, both do things when actaivted
250
Common G⍺ subunits in neurons 3
Specialized 3
Gs: stimulates Adenylyl Cyclase, increases cAMP
Gi/o: inhibits Adenylyl Cyclase, decreases cAMP
Gq: activates Phospholipase C
special:
Gt: photoreceptors
Ggust: taste receptors
Golf: olfactory receptors
251
G-proteins activate
GPCRs do a
G-proteins allow a cell
many pathways
bunch of stuff, response depends on which receptors a cell expresses, which G-proteins they bind, which pathways are
present to be activated
incredible flexibility
252
One neurotransmitter,
Multiple neurotransmitters,
many pathways
same pathway
253
G-protein signaling is
Every aspect of a GPCR pathway
___3+3___ Can all be modulated during development or periods of altered
neural activity
plastic
can be modified by the cell
Expression levels, membrane availability, surface location of:
receptor subunits/isoforms
G⍺βy isoforms
downstream effectors
254
What does m-R signaling do physiologically? 2
Dictated by receptor type, G-protein type,
subcellular location
m-R signalling does a lot of things, so our focus will be on processes that immediately alter:
synaptic function or cellular excitability
255
m-Rs are
Cells: 3
within cells: 3
all over the place
Presynaptic, Postsynaptic, Glia
synaptic, perisynaptic, nonsynaptic
256
GABAB and mGluR have
act as
GABABRs and mGluRs can act to
presynaptic effects
autoreceptors
decrease synaptic release
through the same mechanisms
(activate same G-proteins)
257
GABAB and mGluR postsynaptic effects 2
βy complex directly activates K+ channels (GIRK: Gprotein coupled Inwardly Rectifying K+) and suppresses calcium channels
Gi/o indirectly suppresses NMDA receptor activity
258
Single stimuli tend to
Spillover and Extrasynaptic receptors 2
result in very local neurotransmitter effects
Trains of stimuli (action potentials)
can lead to larger responses
Neurotransmitter may diffuse beyond
the synaptic cleft
