Lecture 10 & 11 Outline Flashcards
What are synapses?
connection b/t 2 neurons (or a neuron & another cell)
- the connection is specialized for the transfer of info
Synapses can be classified in several ways:
1) Functional
- electrical & chemical synapses
2) Location on post-synaptic cell
- axodendritic, axosomatic, axoaxonic
Describe “Synaptic Activity”
causes graded potentials in the postsynaptic cell
- EPSP
- IPSP
EPSP
a DEpolarizing synaptic potential is called an excitatory postsynaptic potential (EPSP)
IPSP
a HYPERpolarizing synaptic potential is called an inhibitory postsynaptic potential (IPSP)
The grand sum of EPSP & IPSP at the axon hillock WILL determine:
if the threshold potential is exceeded & an AP is stimulated
Electrical synapse definition
pass an electrical signal, or current, directly from the cytoplasm of one cell to another through the pores of gap junction proteins
Electrical synapse anatomy
gap junctions: ion channels that connect presynaptic neuron to a postsynaptic neuron
each “connexon” (or hemi-channel) made of 6 “connexin” monomers
2 connexons (half channels) for a functional gap junction
gap junctions from 2 cells must align to forma functional channel
Electrical synapse properties
electrical info (an AP for ex) passes directly b/t 2 cells
- carried by the movement of ions b/t cells (ions)
- small molecules can also diffuse thru GAP junctions (ATP, cAMP, some other 2nd messengers…)
present in some neurons, common in cardiac & smooth muscle
- relatively uncommon in neurons
electrical signal can be bidirectional
fast (VERY short synaptic delay, 0.2 ms)
cells with gap junctions are said to be connected by cytoplasm
allows groups of cells to fire APs nearly synchronously
Chemical synapse definition
use neurocrine molecules to carry info from one cell to the next
Chemical synapse anatomy
presynaptic cell and postsynaptic cell with a synaptic cleft of (20-40 nM) along other things
Chemical synapse properties
specialized form of exocytosis
release of neurotransmitter from PREsynaptic cells to influence electrical activity in POSTsynaptic cell
- neurons communicate with post-synaptic targets
- other neurons
- muscle cells
- glands
estimated 100-600 trillion synapses in brain
- 0.5-1 billion per mm3 in some areas of brain
electrical signal from one neuron is converted to a chemical signal to cross a synaptic cleft, then is often converted back to an electrical signal
What is the difference in size of synaptic cleft in a chemical & electrical synapse?
20-40 nM in a CHEMICAL synapse (distance is farther)
3-4 nM in an ELECTRICAL synapse (the neurons are very electrically close to each other)
What are the many types of neurotransmitters?
Classic neurotransmitters
- Acetylcholine
- Amines
- norepinephrine, dopamine
- histamine, serotonin - Amino acids
- glutamate
- gama-amino-butyric acid (GABA)
“Novel neurotransmitters”
- Peptides
- oxytocin, melanocortin - Purines
- ATP
What receptors do peptides & purines use?
peptides usually act by G-protein c. receptors (GPCRs)
purines act by a receptor channel
What is the general mechanism that leads to the release of a neurotransmitter from a synaptic terminal?
- AP travels down axon
- depolarization opens VG Ca2+ channels
- this allows Ca2+ to enter presynaptic terminals - Ca2+ entry causes some synaptic vesicles to fuse with presynaptic membrane & release their neurotransmitter contents into the synaptic cleft
- Neurotransmitter binds to postsynaptic receptors
- some receptors are ion channels, some are GPCR
- the postsynaptic response depends on the type of receptor (receptor channel or GPCR)
- time taken to diffuse across & cause postsynaptic response is SYNAPTIC DELAY (about 2 ms) - Neurotransmitter is removed from the cleft
What is the difference in the synaptic delay for an electrical synapse & chemical synapse?
chemical synapse: ~2 ms
electrical synapse: ~0.2 ms
therefore, a chemical synapse is gonna be much slower than what you will see @ an electrical synapse
What are the 4 main ways that a neurotransmitter is removed from the cleft?
- DESTROYED in the synaptic cleft by a degradative enzyme or
- TRANSPORTED BACK into the terminal by active transport
- recycled & repackaged back into vesicles - DIFFUSES AWAY from synapse
- TAKEN UP into postsynaptic cell by ENDOCYTOSIS
Describe the 4 steps of synthesis & recycling of Acetylcholine
- ACETYLCHOLINE (ACh) is made from choline & acetyl CoA
- In the synaptic cleft ACh is rapidly broken down into choline & acetic acid by the enzyme ACETYLCHOLINESTERASE
- Choline is transported BACK into the axon terminal by cotransport with Na+ (SECONDARY ACTIVE)
- Recycled choline is used to make more ACh
Acetylcholine described
neurotransmitter at a CHOLINERGIC synapse
neurotransmitter used by
- motorneurons to cause excitation of skeletal muscle
- every pathway of the ANS
- used diffusely throughout the CNS as a neuromodulator
What are the 2 main kinds of receptors for ACh
- Receptor channels (nicotinic receptor)
- called this b/c nicotine binds to this receptor channel & causes it to open so nicotine is angonist for ACh receptor channels - GPCR (muscarinic receptor)
- called this b/c there is a chemical from specific kind of mushroom called muscarin & it acts as an agonist for the ACh GPCR
What can we call receptor channels (nicotinic receptor)?
IONOtropic b/c they allow movement of ion across the cell membrane
What can we call the GPCR (muscarinic receptor)
METAbotropic receptors b/c once a GPCR is activated, it stimulates a whole series of events within a cell - metabolic
Describe the Fast EPSP of Acetylcholine (via nicotinic receptor)
binding of ACh to receptor channel causes:
- opening of channel
- entry of Na+ (& exit of a small amount of K+)
movement of + charge into cell causes depolarization
the postsynaptic depolarization is excitatory = EPSP
FAST!!! (happens after a delay of milliseconds)
Describe the Slow EPSP of Acetylcholine (via muscarinic receptor)
Binding of ACh to GPCR causes:
- generation of 2nd messengers
- activation of kinases
- phosphorylation of proteins in the postsynaptic membrane
- some of the proteins that get phosphorylated are phosphorylation gated ion channels
- phosphorylation gates K+ leakage channels CLOSED (will cause depolarization of MP)
- SLOW (happens after a delay of seconds)
What is a neuromodulator?
slowly, & subtly change the electrical behaviour of a cell
- doesn’t immediately stimulate APs or immediately inhibit them
Ex: might make it easier to bring it to threshold to fire APs or might make it harder
Not all GPCR neurotransmitter receptors will cause closure of K+ channels…
there are MANY POSSIBLE TARGETS in post-synaptic cells
- depends on the cell & the receptor!!
- in some cell types, Na+ leakage channels may be targeted, Ca2+ channels, etc
AKA: just b/c it is a G-protein on post-synaptic cell, doesn’t mean it is gonna be depolarized. It could be hyperpolarized. It can change shape of AP, it is a highly variable response
Describe Norepinephrine
called a NORADRENERGIC synapse
neurotransmitter used diffusely throughout the CNS & by the sympathetic branch of the ANS
several types of receptors
- all are GPCR (ALPHA & BETA RECEPTORS)
- variable effect b/c we can phosphorylate a # of post-synaptic channels
NO ligand-gated ion channels
Glutamate
called a GLUTAMATERGIC synapse
main EXCITATORY neurotransmitter used throughout the CNS
What are the 2 main types of glutamate receptors?
Receptor channels (IONOtropic)
- NMDA receptor
- (N-Methyl-D-aspartate) - AMPA receptor
- (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)
GPCR (METAbotropic glutamate receptors)
- several subtypes
Glutamatergic receptor: AMPA receptor (ionotropic)
- glutamate will bind to the this receptor, cause it to open
- allows Na+ to pass (some K+)
- depolarizes postsynaptic cell (when it is activated)
Glutamatergic receptor: NMDA receptor (ionotropic)
- allows Na+ AND Ca2+ to enter the postsynaptic cell (some K+ leaves)
- inward movement of Na+ & Ca2+ depolarizes cell (EPSP)
- is normally blocked by Mg2+ (@ RMP, so even if glutamate binded to it, it still can’t open), but Mg2+ is ejected when membrane depolarizes
Why is the NMDA receptor (ionotropic) special?
- ligand-gated & behaves like a “voltage gated” channel
2. also allows Ca2+ into the postsynaptic cell
Describe Gamma-amino-butyric acid: GABA
called a GABAergic synapse
main INHIBITORY neurotransmitter used throughout the CNS
- makes MP more (-) –> father from the threshold so harder to fire AP
What are the 2 kinds of receptors for GABA?
- Receptor channel: IONOtropic GABAa receptor
- GPCR: METAbotropic GAPAb receptor
- effect is variable, depending on channels phosphorylated…
Describe the fast IPSP of GABA
binding of GABA to GABAa receptor channel causes:
- opening of channel
- (-)ly charged Cl- ONLY allowed to enter cell
movement of (-) charge into cell causes HYPERpolarization
the postsynaptic hyperpolarization is INHIBITORY: = IPSP
FAST - b/c it is a receptor channel (not as fast as electrical synapse since this is a chemical synapse though)
- quick to happen & then over very quickly
- characteristic of ligand-gated channel
Which synaptic receptors, a receptor-channel or GPCR, causes a faster postsynaptic response? Why?
Receptor channel - b/c it has less steps to carry out
Receptor channels are…
very fast EPSP/IPSP
Neuromodulators are the way that GPCRs…
can change behaviour of neurons
- refers to actions of a GPCR
GPCRs are slow & goes on for a long time b/c…
whole process has to go through these biochemical pathways (& LONG LASTING change in the behaviour of the neuron)
- that is why we use the word neuromodulator
Neurotransmitters definition
create rapid, short-acting fast synaptic potentials
Neuromodulators definition
create slow synaptic potentials & long-term effects
Describe Electrical synapses
- FAST & simple (0.2 m/s)
- NO neurotransmitter involved
- close positioning of a pre & post synaptic cell - requires gap junctions
Describe chemical synapses
relatively complex, SLOWER (2 m/s or longer (sec to min if it was caused by a GPCR) would be the time it takes for a neurotransmitter to diffuse across cleft, bind to a receptor channel & cause a postsynaptic potential
electrical signal from 1 neuron is converted to a chemical signal to cross a synaptic cleft, then is often converted BACK to an electrical signal (depol = excit, hyper = inhib)
- allows excitatory signals to become inhibitory
- allows modulation of signals (switch from single AP to tonic to bursting: info processing)
- very efficient: a FEW molecules of neurotransmitter can have a LARGE electrical effect
wide variety of receptors, even for a single neurotransmitter
- for ex, GABA has at least 20 diff receptors (channels, GPCRs & isoforms of these)
Partial summary for neurotransmitters & receptors (physiological conditions): Receptor Channels (nicotinic receptor)
Receptor channels
- AChR: Na+ (& a little K+) depol
- NMDA: Na+, Ca2+, (K+) depol
- AMPA: Na+ (& a little K+) depol
- GABAa: Cl- hyperpol
Partial summary for neurotransmitters & receptors (physiological conditions): GPCR (muscarinic receptor)
GPCR
- *AChR
- Norepi
- Glutamate
- GABA
variable effects: phosphorylation can open or close MANY diff types of channels
when the muscarinic receptor is activated it causes generation of 2nd messengers & causes activation of protein kinases & one of the things that gets phosphorylated are K+ leak channels
- as those K+ leak channels close, they cause a depolarization of the MP
What is Synaptic Integration?
refers to the idea that whether or not the postsynaptic neuron fires an AP depends on the grand sum of (all the excit & inbib synapses) synaptic activity acting on the cell
What are the # of factors that will play important roles in how the synaptic info will “add up” in a network of neurons?
- AP frequency
- Divergence & convergence
- Temporal & spatial summation
- Location of synapses on postsynaptic cell
The frequency of AP firing indicates the…
STRENGTH of a stimulus
Weak stimulus releases…
little neurotransmitter
- sensory neuron detects a little bit of pressure, then there will be a small EPSP or small GP
Strong stimulus causes…
MORE APS & releases MORE neurotransmitter
- sensory neuron detects a larger pressure, then there will be a larger GP
What are the 4 key points of the AP Frequency?
- Both stimuli enough to bring a cell to the threshold & fire APs
- Amplitude of the GP is proportional to the SIZE of the stimulus
- Amplitude of these APs is the same b/c remember APs are ALL-or-NONE
- if you stimulate it above threshold just a little bit or if you stimulate it above by a lot - the amplitude of the AP is still the same - The thing that changes is the FREQUENCY of the APs
Divergence vs Convergence
(a) In a DIVERGENT pathway, 1 presynaptic neuron branches to affect a LARGER # of postsynaptic neurons
(b) In a CONVERGENT pathway, many presynaptic neurons provide input to influence a SMALLER # of postsynaptic neurons
What is an example of Covergence?
Purkinje neuron (specialized) may have 1x10^6 synaptic inputs - 1 purkinje neuron in your cerebellum may have up to a million synaptic inputs (uncommon - most neurons don't have that many synaptic neurons)
Define Temporal Summation
occurs when 2 GPs from 1 presynaptic neuron occur close together in time
Describe Temporal summation (i.e. no summation vs summation)
(a) No summation - 2 subthreshold GPS will not initiate an AP if they are FAR apart in time
(b) Summation causing AP
- if 2 subthreshold potentials arrive at the trigger zone within a SHORT period of time, they may SUM & INITIATE an AP
Define Spatial Summation
occurs when the currents from NEARLY SIMULTANEOUS GPs COMBINE
Describe Spatial Summation (i.e. summation vs. postsynaptic inhibition)
(a) Summation of several subthreshold signals results in an AP
1. 3 excitatory neurons fire
- their GPs separately are all BELOW threshold
2. GPs arrive at trigger zone together & SUM to create a suprathreshold signal
3. An AP is generated
(b) Postsynaptic inhibition
- an inhibitory presynaptic neuron prevents an AP from firing
1. 1 INHIBITORY & 2 excitatory neurons fire
2. the SUMMED potentials are below threshold, so NO AP is generated
What is Spatial Summation ultimately?
ultimately, the process is the GRAND SUM of EPSP & IPSP, which is what is going to determine whether or not this cell gets to the threshold to fire its AP
Define Axodendritic
if a synapse is found on the dendrite of a neuron
- an axon on 1 neuron making a synapse on the dendrite of another
Define Axosomatic
synapses on the soma of that cell
- takes LESS time to travel (closer to the trigger zone than axodendritic one)
- causes a larger EPSP @ trigger zone b/c it has LESS distance to travel
Define Axoaxonic
a synapse on the axon of that post-synaptic cell
- happening right on the trigger zone itself
- most powerful of the axondendritic & axonsomatic b/c the EPSP doesn’t have to travel any distance across the cell membrane - it’s already there
- so it has a huge effect on whether or not this post-synaptic cell is going to fire an AP
Define Asoaxonic (presynaptic)
presynaptic facilitation
presynaptic inhibition
a synapse that is DIRECTLY on a synaptic terminal
- ONLY determines/modifies the amount of neurotransmitter that is released by these synaptic terminals
If all things were equal b/t axodendritic synapse & axosomatic synapse - by the time that EPSP reached the trigger zone the synapse on the axosomatic will…
cause a LARGER EPSP @ the trigger zone b/c it has LESS distance to travel
How does the axoaxonic determine/modify the amount of neurotransmitter released by these synaptic terminals?
- if the axoaxonic (presynaptic) is excitatory & firing at a very high rate, it is depolarizing that synaptic terminal all the time (which increases the amount of Ca2+ that is in that synaptic terminal - will activate some of the VG Ca2+ channels & allow a high amount of intracellular Ca2+)
- so when the neuron fires an AP & invades the terminal you ALREADY got a baseline level of Ca2+ & now you get a bigger wave of Ca2+ & so now you have more Ca2+ in that presynaptic terminal it is going to release more neurotransmitter at this synapse
- AKA if it is excitatory the axoaxonic synapse will facilitate the release of neurotransmitter
- if the axoaxonic (presynaptic) is inhibitory & its hyperpolarizing that synaptic terminal - & the AP travels down the axon, even though it invades this synaptic terminal, it’s not gonna depolarize it enough to activate the VG Ca2+ channels & you won’t get a lot of intracellular Ca2+
- so this time, axoaxonic synapse will inhibit the release of neurotransmitter
What is the beauty of the axoaxonic (presynaptic) system?
it is very subtle regulation, b/c it is being regulated by another synapse (so it is a subtle form of the regulation of the release of neurotransmitter onto the post-synaptic cell)
What is synaptic plasticity?
is the ability of neurons to change synaptic strength
- potentiation (stronger over time)
- depression (weaker over time)
Describe Long-term potentiation (LTP) & long-term depression (LTD)
widely thought to underline the process of learning (acquisition of new memories - NOT the storage)
- happens in MANY TYPES OF NEURON
the best studied neurons that exhibit LTP in mammalian brain are IN THE HIPPOCAMPUS
Who is Brenda Milner?
a neuroscientist from Montreal Neurological Institute, discovered that the hippocampus was critical for ACQUISITION OF MEMORIES
Describe patient H.M.
patient H.M. (a boy who had an injury & developed epilepsy then realized it was in the temporal lobe & stopped it)
- but the hippocampus is in the temporal lobe
- epilepsy was fixed but could no longer ACQUIRE NEW MEMORIES (old mems were in tack before surgery)
- called a DECLARITIVE MEMORY
- trouble with maps (got lost) b/c you need an intact hippocampus
- could learn new motor skills but couldn’t remember what he had for breakfast the other day
- Brenda Milner discovery
What are the several mechanisms of LTP (as it occurs in the hippocampus - LTP in hippocampus is critical for acquiring new declarative memories)?
- the following ex of LTP happening b/t 2 groups of neurons is initiated by a period of high frequency APs in the presynaptic neurons
- LTP is seen as a LONG LASTING POTENTIATION OF THE EPSP (increase in depolarization caused by single presynaptic AP)
- requires NMDA & AMPA receptors in the post synaptic membrane
- Metabotropic glutamate receptors also play a role
- rise in intracellular Ca2+ is crucial
- pre & post synaptic changes
What are the 3 types of glutamate receptors that play a key role in LTP?
- Metabotropic (GPCR)
- AMPA (carries mostly Na+) - causes depolarization
- NMDA (carries Na+ AND Ca2+) REMEMBER THE CELL MUST BE DEPOLARIZED IN ORDER TO GATE NMDA-R OPEN)
What are the steps to induce LTP?
happens short term (mins –> 10s of mins)
- High frequency stimulation (of APs) of presynaptic neuron release of glutamate (into synaptic cleft which makes it available to bind to those postsynaptic receptors)
- (Glutamate binds to AMPA receptors causing them to open) Activation of AMPA receptors leads to depolarization (Na+ enters) of the post-synaptic neuron via EPSPs
- Depolarization releases block of the NMDA receptor (this allows the NMDA to conduct Ca2+ into the cell)
- Continued synaptic activity also activates metabotropic glutamate receptors
- Activates a 2nd messenger pathway that releases intracellular stores of Ca2+ ions (b/c remember some GPCRs will cause release of intracellular Ca2+)
So we have 2 mechanims:
1) Ca2+ comes in
2) Releasing Ca2+ from intracellular stores
* these 2 TOGETHER cause a massive increase in the intracellular Ca2+ concentration
4) So…the postsynaptic terminal experiences LARGE INCREASE IN INTRACELLULAR CA2+ CONCENTRATION
5) Increased Ca2+ leads to activation of several kinases (short-term)
1. Phosphorylation of AMPA receptors, increasing affinity & conductance (bring glutamate more tightly & then open wider - so now AMPA glutamate receptors allow more Na+ to come into the cell)
- (Postsynaptic neuron has a store of AMPA receptors & once activation happens by increase intracellular Ca2+) Insertion of new AMPA receptors (in postsynaptic cell which allows glutamate to have a larger EPSP, glutamate will bind to more receptors)
- Generation of RETROGRADE MESSENGERS that facilitate release of vesicles (nitric oxide) (with this increase in intracellular Ca2+ it will activate enzymes that synthesize NO)
All together (for LTP) we have…
more neurotransmitter released & every molecule of neurotransmitter now causes a larger EPSP, in this way we can increase the size of the EPSPs at this synapse
What is the long term maintenance of synaptic potentiation?
- (what happens after is this synapse can stay more powerful for a long period of time b/c the post synaptic cell) Changes in gene expression (expresses new proteins)
- (The postsynaptic cell & presynaptic cell can split & now form 2 synapses where there were 1) Creation of new synapses
- (Results in :) Co-ordinated pre & post-synaptic effects
So, the amplitude of EPSPs are bigger
Sometimes you can see a glial cell that’s wrapped around that synaptic terminal & it does this for 2 reasons:
- Provides physical strength to that whole structure
- Help encapsulate the whole synapse so that it forms a tighter structure - so it CAN prevent (depending on the top of synapse) the leakage of neural transmitter out of there (so in some synapses, it can help make the whole thing a little more efficient)
