Unit 1 Flashcards
Definition of specialization.
Adaptation to serve a particular function
What is the nervous system?
network of cells that transmit signals throughout the body
What is a neuron?
computational unit, the fundamental element that performs a task or makes a decision
What did Camillo Golgi believe about neurons?
They were one distributed structure
What did Ramon y Cajal believe about neurons?
Many separate structures that communicate, “Dynamic Polarization”
What does the Neuron Doctrine state?
neurons are seperate cells that communicate
How can neurons achieve complex?
by communicating with each other
What are synapses?
sites of communication
What does more neurons and connections means?
more specialization , more varied activity, more complex thought and action
What did Ramon y Cajal discover?
“Dynamic Polarization”, something is moving through the cell
What are Nuerites?
-a projection from a neuron’s cell body
-specialization for transmitting signals
What are the functions of the cell body/soma?
-contain nucleus, genetic material
-house organelles
-transcription and translation
What do neurites and cell bodies have in common?
both can house organelles and complete translation
Why is it important for neurites to be able to complete translation?
DNA is pushed out into Nuerites where it can be made into protein on demand. This is important for changing the functions and the communication for neurons
What does Cajal’s “polarization” refer to?
neurites have 2 varieties
what are the two varieties of neurites?
dendrites (input) and axon (output)
Describe the relationship between dendrites and axons.
Typically, dendrites receive incoming information (from synapses)
When neuron decides to activate, it transmits that information downstream via axon (to synapses)
What type of dendrites connect to soma?
primary
what gives dendrites their arboreal appearance?
forked branches
What is a collection of dendrites of a cell called?
its arbor
What does proximal refer to?
closer to soma
What does distal refer to?
farther from soma
Which neurite is thicker proximally than distally?
dendrites
Which neurite can be spiny? What happens at these spines?
dendrites, synapses form
Describe spines of dendrites
-can form synapses
-afford compartmentalization (to regulate its signaling)
-spines can be grown and eliminated
-sites of communication between cells
-can be effected without effecting entire dentrite
Compare the angles of which branching occurs in each type of neurite. Also describe the difference in branching patterns
Dendrites: < 90 , arboreal
Axons: = 90 , sprawling
Which neurite can appear like beads on a string at high magnification?
axon
What are branches of axons called?
collaterals
Which type of brain matter is full of axons?
white matter
What is tractography?
mapping direction of white matter connections
What type of brain matter is full of cell bodies?
gray matter
Which matter is interior vs exterior of the cerebral cortex? What connects cell bodies?
gray matter is exterior, white matter is interior
axons in white matter connection cell bodies in gray matter
What does AIS stand for? What does it do?
Axon Initial Segment
-proximal region of axon
-attaches to axon hillock
-where signal in axon is generated
-enriched in proteins for sending signal down axon
What is the axon hillock?
site where axon connections to soma
Describe axon terminals
-swollen endings of axon
-aka bouton
-half of a synapse
-site where neural activity is transformed into neurotransmitter release
What is a neurotransmitter?
chemical released by neuron to convey neural activity
Describe what is meant by “Boutons en passant”
-“passing buttons”
-sites for neurotransmitter release
-can form along axon, not solely terminal
-gives rise to “bead on a string”
Describe a synapse. What is packed into synaptic vesicles?
-apposition of axon terminal and NT receptors
-NT
What is the gap between 2 cells where NT is released called?
synaptic cleft
What is the exception to dynamic polarization?
axo-axonic synapse
What are the three types of synapses?
-Axo-dendritic
-Axo-somatic
-Axo-axonic
What is a Neuromuscular Junction?
-neurons signal not just to other neurons, but also to muscle
-special synapse between neuron (motor neuron/ motoneuron) and muscle
-high density of receptors ensures reliable response (muscle is sensitive)
What does IHC stand for?
Immunohistochemistry
What is the utility of the Golgi Stain?
stains/ colors neurons fully
What conclusion did the golgi stain help make?
neurons are separate cells that communicate (neuron doctrine)
What reflects function?
structure
What is histology?
addresses microscopic structure of tissue
What is the H&E stain?
Hematoxylin: Wood Extract
-stains nucleus purple
Eosin: synthetic dye
-stains cytoplasm pink
What is the function of the immune system?
a system for detection of specific proteins
What is IHC?
-powerful chemical approach to study tissue (histology) using antibodies of the immune system
-uses antibodies as labels to visualize specific structures
What is an antigen?
substance eliciting immune response
What is an epitope?
-part of antigen bound by antibody
-antigenic determinants
How do covid antigen tests work? What is a positive control?
-recognize the N protein of viral particles
-Test Line: mass produced antibodies that bind (and thereby report) covid virus
-Control Line: antibodies that bind (and report) other antibodies (a form of positive control which reports the experiment could have worked)
How could we use the covid test approach to label synapses?
-we produce antibodies that bind epitopes in a synapse
-IHC
-turn elements unique to synapses into antigen
Describe a pyramidal cell.
-apical dendrite
-basilar dendrites
-common in layered cortical structures, samples from above and below
Describe bipolar cells.
connect outer and inner retina, sort visual info into layers
Describe chandelier cells
-inhibitory cell
-specifically targets AIS of many neighboring cells
-shuts off patch of neurons
-axoaxonic synapses
Describe double boquet cells
-influence a column of activity in cerebral cortex
Describe starburst amacrine cells
support spatial processing in retina
Describe Tufted Cells
-dendrites densely fill
-patch of odor-specific axons
-in olfactory bulb
What is the Rosehip neuron?
-discovered in 2018
-found in human cerebral cortex
-discoverer claims cell’s center looks like a rose the shed it’s petals
What are the two types of cells in the nervous system?
neurons and glia
What is Neuroglia?
“nerve glue”, originally thought to control local environment of neurons
What is the same about glia and neurons?
they are equally as varied and numerous
What is different about glia and neurons?
glia
-no synapses
-less excitable
-not typically polarized
Which type of glia contact blood vessels to regulate blood flow and support the blood-brain-barrier?
Astrocytes (“star cells”)
Why are Astrocytes important?
-support neurons locally
-provide nutrients
-balance ions, including pH
-sequester neurotransmitter, remove from cleft (help prevent seizures)
-thereby regulate activity of neurons
What is the function of the end feet of Astrocytes?
help make sure that chemicals in the bloodstream don’t have free access to neurons
Describe the function of Ependymal cells.
-line cavities in nervous system
-motile cilia create flow in cerebrospinal fluid, providing nutrients and removing waste
Describe the function of Myelinating cells
-wrap axons of neurons with myelin, rich in lipid, to provide insulation, help signals propagate
-different glia myelinate in brain/spinal cord vs. peripheral nervous system (nerves in body)
-found throughout brain, but dominate and give white matter its white (fatty) look
What are Myelinating cells called in the brain/SC vs in the PNS?
Brain/SC: oligodendrocytes
PNS : Schwann cells
What is the function of Microglia?
-immune cells of the central nervous system
-small and migratory
-recruited to cite of injury
-perform phagocytosis (ingestion of material)
-involved in healthy nervous system function (normal turnover, clearing room for new synapses)
In summary, why are glia important?
-perform essential complementary functions to neurons
-glia don’t use synapses but do signal and influence neural activity
What is used to record voltage on scalp?
EEG - electroencephalography
What is voltage?
-electric pressure, electric potential difference
-measure of capability to move charge between two points
What are voltages around the scalp really representing?
shadows of voltages across membranes of individual neurons
What is Membrane Potential (Vm)?
voltage or electrical potential across a membrane
Which part of the neuron is polarized?
-plasma membrane
-interior tens to be negative relative to outside
What is the cost to generating electrical signals?
energy
How much of our energy consumption goes to brains? What is it mostly used for?
energy, most goes to creating voltage
What was the Balloonist Theory?
-ancient view: brain pumped signals to muscles
-Galen and Descartes
-fluid in ventricles inflated muscles via hollow nerves
What is signaling?
transmitting information about an event or condition elsewhere
Describe molecular signaling
-ubiquitous
-potent
-often slow
What was the signaling research done by Galvani?
Electricity as a neural signal (Frankenstein)
Describe fast signaling with electricity
-charged particles, when free to flow, can transmit quickly through electricity
-an individual charged particle moves little relative to the electromagnetic wave (which can approach the speed of light)
What work was done by Hodgkin and Huxley?
-1930’s and on
-electrical recordings from squid giant axon
-first direct measurement of membrane potential
What is a ganglion?
cluster of neuron cell bodies
What are nerves?
collection of axons
How are neurons primed to signal electricity?
maintain a resting membrane potential
What is the intracellular and extracellular solvent?
water
What conducts electricity in the nervous system?
solutions like cytosol and cerebrospinal fluid
Why did the demo only light up when salt was added?
dissolved ions conduct electricity
Why do sports drinks fight cramps?
-replenish ions depleted during exercise
-helps nerves and muscles conduct electricity
What is conductance(g)?
-the degree to which a material conducts electricity
-inverse of resistance (R)
Why does the light turn on?
-conductance is increased, meaning resistance is lowered, which means more current (I) flows and the light needs sufficient current to turn on
What is Ohm’s Law?
V=IR
-for fixed voltage, current increases as resistance decreases
I=V/R
R=V/I
V=I/g
Why is Ohm’s Law important?
tells us..
1. generally, current and voltage are inextricable (if charge can’t move, there’s no potential to move charge)
2. practically, how voltage and current relate at a given resistance
What is the voltage difference across the leads of an isolated battery?
-there is no circuit, current cannot flow, there is no voltage
Explain the Ohm’s Law analogy of the zebra fish rollercoaster
water = charge
voltage = pump
current = speed of wheel=
resistance = tube/valve
Where does resistance come from in the case of a cell?
plasma membrane
Describe the plasma membrane structure
-made of molecules that behave like soap
-polar end is hydrophilic
-nonpolar end is hydrophobic
-made of phospholipids
-insulator
What does it mean to be an insulator?
material in which current does not flow
Thin insulator is recipe for?
capacitor
What does a capacitor do? How does this relate to the plasma membrane?
-stores charge
-opposite charges attract across thin insulator
How is the capacitor represented in the roller coaster analogy?
-capacitor slows down the movement of charge across the membrane
-represented by tank on top
-charge takes the path of least resistance
What puts charge on the plasma membrane?
voltgate (electric pressure)
What does charge on the membrane affect?
proteins in the membrane
How does charge cross the membrane?
proteins in membrane offer channels for ions to flow, creating current (and voltage)
Describe the proteins in the membrane
special amino acid makeup and special synthesis
Why is the alpha helix useful?
helps arrange hydrophobic R’s, this portion of protein is in the membrane
How do neurons create voltage?
-with pores present, ions diffuse across membrane
-dissolved ions move randomly and end up evenly distributed
-ions flow down concentration gradient (to areas of relatively low concentration)
-diffusion can create current (net flow of charge)
Is the balancing of concentrations of ions fast or slow?
slow- only a tiny fraction of ions diffusing will create voltage
What else can cause ions to move?
imposed voltage
What if diffusion and membrane voltage simultaneously push ions?
-combination of diffusion and electrical filed is called electrochemical gradient, which ions move down
What is equilibrium potential (E)?
-membrane potential at which there is no net diffusion of ions down concentration gradient
-reversal potential
What tells us how strongly ions will flow?
difference between the equilibrium potential and the actual voltage, AKA driving force
What is the equation for driving force?
Vdf = Vm - Eion
What is the Nernst Equation?
formula for calculating the equilibrium potential Eion
review slides 84-92 of lecture 3
What is essential for polarizing the membrane?
maintaining ion concentrations
How is energy turned into electrical signals in neurons?
Ion exchange
Describes the sodium-potassium pump
-enzyme that consumes energy stores (in ATP bonds)
-exchanges 2 Na+ ions inside cell for 2 K+ ions outside cell
What type of ions are accumulated in nuerons?
potassium
What does changing concentration of ions in solution that bathes neurons affect?
their Vm
What happens when K+ is elevated outside of neuron
balancing K+ inside and out, so Vm moves towards 0
What glial cell is in charge of balancing extracellular potassium?
astrocytes
What would membrane potential be if the plasma membrane was only permeable to K+?
-80mV
What are most neurons Vm at equilibrium?
-60 or -70 mV
Neurons can both expel and accumulate ions. Describe the concentrations of Na+, K+, Cl-, and Ca++ inside and outside the cell
Na+ is much higher outside
K+ is much higher inside
Cl- is much higher outside
Ca++ is much higher outside
Are equilibrium potentials the same for all ions?
no, review typical concentrations in neurons
lecture 3 slide 105
What equation allows us to consider multiple ions together?
Goldman equation
review lecture 3 slide 109
What is permeability?
-ease with which ions cross membranes
-proportional to that of potassium
Which neurons have a higher influence on the membrane potential?
ones that flow more easily
potassium
Describe the permeability of potassium, sodium, calcium and chloride
-Potassium has high permeability
-Sodium has low permeability
-Calcium and Chloride flow negligibly
What is happening during feedback?
output is being used as input
What is happening during positive feedback?
when output is amplified through its effect on system that gave rise to it
What is an example of positive feedback?
microphone + speaker
What is happening during negative feedback?
when effect counteracts process that gave rise to it
What is an example of negative feedback?
Thermostat- room warms from “set point” temp. AC turns on to cool back to set point
What is a closed loop system?
A system running with feedback
What is an open loop system?
A system running without feedback
Why is open loop problematic?
errors can accumulate, no method to restore course
What sets resting membrane potential?
K+ and Na+
K+ flows outward, pulling Vm negative
Na+ flows inward, pulling Vm positive
each ion pulls the membrane potential towards its reversal potential
and each ion’s strength dictated by how permeable the membrane is to that ion
So, resting membrane potential is defined by the permeability of ions
Describe leak channels.
Leak channels are always open, contribute to resting membrane potential
Compare K+ and Na+ leak channels
K+ leak channels are much denser than Na+ leak channels
This is why resting membrane potential is dominated by outwards K+ flow
Describe gated channels
capable of opening and passing ions
Why does charge build up on the membrane of a cell?
capacitance
What are Voltage-Gated ion channels?
ion channels that open and close depending on voltage
create feedback systems
Vm determines whether or not they open or close
How does the ion channel detect changes in voltage?
Linked ion pore and voltage sensor with selectivity filter
as voltage changes, so do the forces acting on the charged domain
What influences channel conformation of a voltage gated ion channel?
membrane potential
How does a negative resting membrane potential impact a voltage gated channel? What happens if Vm depolarizes?
charged (+) side chains pulled toward inside of cell
if Vm depolarizes (becomes more +), charged segment is released, and channel opens
Describe how positive feedback occurs from sodium flow?
Rising Vm causes the voltage gated channels to open, allowing Na+ to move into the cell.
As Na+ moves into the cell, Vm continues to rise but now more quickly
What happens if membrane potential does not reach threshold at which voltage-gated Na+ channels open?
-no positive feedback
-no A.P.
-return to rest
What happens if membrane potential does reach threshold?
-positive feedback
-explosive depolarization
Describe the action potential
-called “spike”, “nerve impulse”, or “discharge”
-reversal of charge relative to extracellular space
-travels down axon
-lasts on order of 1 msec
-drives communication across synapses
Why does action potential of a neuron stop near +50mV?
-AP involves increase in P(Na)
-As seen in Goldman equation, a very high sodium permeability will move Vm near E(Na) (+62mV)
-Overall, the dominant sodium permeability moves Vm close to ENa
How do neurons communicate down long, thin axons?
-High resistance of long cables (like straw or axon) requires large voltage to induce current flow
-Resistance of a neurite increases as it gets longer
-Without large de-polarization due to the AP, depolarization in the soma would affect the distal axon minimally
What is Myelin?
-lipid insulation of axons produced by glia
-also helps neurons communicate down long, thin axons by ensuring current upstream produces a potent depolarization and the next node depolarizes strongly
What must happen in order for an AP to propagate down a myelinated axon?
each node must push the next past AP threshold
What are Nodes of Ranvier?
myelinating glia leave gaps in myelin where channels cluster
What is AP jumping from node to node called?
“Saltatory Conduction”
How do we break the relationship between ionic currents and membrane potential?
Voltage Clamps
What does a voltage clamp actually do?
-Can set the voltage and clamp the cell there (Negative feedback)
-step Vm to activate voltage-gated channels
-measuring the current at the injecting electrode reveals what the membrane was attempting to do
What does recording across the entire membrane in voltage clamp reveal?
its conductance, which reflects the number of open channels
What is a more modern approach of the voltage clamp?
“patch=
-can directly measure when a channel or channels open and close at a particular voltage
-can measure unitary conductance of a channel (how much flow a single channel can generate)
Why doesn’t Vm stay at E(Na) when voltage-gated sodium channels open?
This wouldn’t be useful for signaling more than once
1. Sodium channels close themselves
2. Potassium channels help return to rest
Describe inactivation.
-Once activated by depolarization, voltage-gated sodium channels close (despite membrane potential) through inactivation
-The channel’s pore is blocked by a “ball” of amino acids
List the transitions through Inactivation
- Activation
- Inactivation
- Deinactivation
- Repeat
What type of feedback is used for voltage-gated potassium channels?
negative feedback
What is a Delayed Rectifier?
-opens when cell is depolarized
-causes hyperpolarization (neg. feedback)
-close slowly
-“Delayed” because it opens after the voltage-gated sodium channels
-“Rectifier” because it preferentially passes outward current (due to opening when Vm is positive)
Why is hyperpolarization imporant?
Gets neuron ready to spike again
What are re-polarization mechanisms and what do they do?
-sodium inactivation and delayed rectifier
-let neurons fire “trains” of action potentials
What does stronger depolarizing input cause?
faster rate of firing action potentials, pushes Vm back to threshold quicker after each AP
What is Tetrodotoxin used for and what does it do?
Pufferfish use for defense, blocks Na+ channels
What are Alpha- and beta- toxins used for and what do they do?
used by scorpions to capture prey, shifts opening and closing of Na+ channels
What is Dendrotoxin and what does it do?
Used by Mambas to capture prey, blocks K+ channels
What is Apamin and what does it do?
Used by honey bees for defense, blocks K+ channels
Why are naturally-occurring toxins useful?
Useful for manipulating toxins in the lab
What is a gap junction?
portal connecting cytosol of two neurons, allows direct ion flow from one neuron to another
What is necessary for axon survival?
local translation, produce proteins needed at synapse and for metabolic support
Describe growth cones in developing axons
structures at the end of axons that elongate axon. use local translation for steering
Why doesn’t Vm stay at E(Na) when voltage-gated sodium channels open?
- sodium channels close themselves
- potassium channels help return to rest
What were the beliefs of Golgi vs. Cajal, and what is true?
Golgi: Neurons are all connected as a single structure (reticular)
Cajal: Neurons are connected but distinct cells
The truth (for now) is somewhere in between
How do sodium channels close during inactivation?
The channels pore is blocked by a ball of amino acids
Describe a chemical synapse.
-Synapse that signals through release of chemical (NT)
-Many NTs can be released
-Vesicles reflect size of what is being released
-Larger molecules have “denser” vesicles
Describe an electrical synapse.
-Synapse that directly transmits electricity
Describe the active zone.
presynaptic site of NT release, site where vesicles “fuse” with plasma membrane and dump NT
Give an overview of chemical synapse transmission.
- Neurotransmitter synthesis
- Load NT into synaptic vesicles
- Vesicles fuse to presynaptic terminal
- NT spills into synaptic cleft
- NT binds to postsynaptic receptors
- Electrical and/or biochemical response elicited in postsynaptic cell
- Removal of NT from synaptic cleft
Name the categories of NeuroTransmitters.
Canonical NTs
- Amino acids
- Amines
- Neuropeptides
Non-canonical NTs
What are amino acids?
small building blocks of proteins are co-opted
What is unique about neurons that release amino acids?
have special proteins that load them into vesicles
eg. glutamate, GABA, glycine
What are monoamine NTs?
small organic molecules
What is unique about neurons that release monoamines>
have special enzymes to synthesize them
eg. dopamine (DA), acetylcholin (ACh), norepinephrine (NE), serotonin (5-HT), melatonin
What are neuropeptides?
small proteins, typically loaded into oblong, dense-core vesicles
tend to act in paracrine fashion
eg. dynorphin, enkephalins (endogenous opiods), oxytocin, vasopressin, substance P
What does it mean to act in paracrine fashion?
diffusing both across synapses and to cells nearby
What are two exampleds of noncanonical NTs? Describe them.
Nitric Oxide: gaseous, paracrine signal, released by postsynaptic neuron (retrograde NT) through membrane (no vesicles) in response to NT
Anandamide: hydrocarbon chain (fatty acid) in the endocannabinoid (eCB) system, retrograde signal
Describe Neurotransmitter synthesis and storage.
-neuropeptides usually packaged outside of terminal and transported
-amino acids and monoamines often packaged at the presynaptic terminal
Why is vesicle loading at the terminal most effective?
amino acids are found at terminal and most monoamines can be synthesized from amino acids
Describe the two mechanisms that can be used to transform an action potential into NT movement from vesicles to synaptic cleft
- Calcium channels (AP to calcium)
- Calcium-sensitive SNARE complex (calcium to vesicle fusion)
What is unique about calcium channels open?
Because calcium levels are so low in the neuron, when calcium channels open the concentration of Calcium DOES meaningful change
Why are potassium and sodium channels different from calcium channels?
they are so abundant on each side of the membrane that ions flow through channels affects concentrations negligibly
How do mitochondria interact with Calcium?
Mitochondria accumulate calcium through pumps (another reason our brains demand energy) removing it from the cytosol
What are Calcium chelators?
molecules that bind with metal ions, help by binding free calcium
Describe voltage-gated calcium channels?
Like voltage-gated sodium channels, have pore-forming and voltage-sensing domains
Describe voltage-gated calcium channels.
-have pore-forming and voltage-sensing domains
-depolarization causes them to open
-family of channels (don’t need to know members) with different sensitivity to voltage and different locations in neurons
Why are Ca2+ channels a critical part of the chemical synapse?
they elevate local Ca2+ for NT release (fusion of vesicles)
Describe the SNARE complex
- synaptotagmin 1 is a “Calcium sensor”
- once activated by Ca++ synaptotagmin causes SNARE proteins on vesicle and plasma membrane to drive fusion
- fusion of two lipid bilayers makes contents of vesicle free to leave presynaptic terminal
How are voltage gated calcium channels activate?
by depolarization down the axon (typically from action potential)
Why do delayed rectifiers close slowly?
Largely unsolved, but ball-and-chain inactivation also occurs in some K+ channels, is thought to generally be faster than conformational change in the pore
What is the result of calcium binding to synaptotagmin?
causes conformational change that bends membrane, leads to vesicle fusion
What is GluSnFR?
engineering protein fluoresces more when binding glutamate
What is flourescence?
-absorbing light of short wavelength and emitting light of longer wavelength
How are engineered proteins expressed in neurons?
Through transgenesis- trasfer of foreign DNA
What are the take homes about GluSnFR?
-engineering proteins reveal NT by binding and changing fluorescence
-same strategy used for imaging neural activity (via calcium) and for detecting many NTs
What depolarizes a neuron to AP threshold in the first place?
often, other neurons
Describe the channel at an electrical synapse.
Connexon- formed by six connexins
Cells are electrically coupled
Ions flow from cytoplasm of one cell to cytoplasm of another cell (bidirectional)
What is a post-synaptic potential?
action potential from Cell 1 causes depolarization in Cell 2
What do electrical synapses cause postsynaptically?
voltage changes
What are the responses to a chemical synapse shaped by?
-spiking properties
-NT identity
-NT receptors
What are NT receptors?
Receptors in the membrane whose ligand is a NT
What is a ligand?
The molecule that binds the receptors
Describe the relationship between NT and receptors.
-Receptors are specific for NT
-One NT can bind various receptors
What are the two types of NT receptors>?
- Ligand-gated ion channel (ionotropic)
- Metabotropic Receptor
Describe ligand-gated ion channels
-these are usually 5 subunits (multimer-pentamer)
-each subunit can be coded by a different gene (heteromeric)
How is channel diversity created in Ionotropic receptors?
Multiple genes code for each of the subunits. Therefore, can mix and match subunits.
How many times can subunits cross the lipid bilayer?
4 times
How do ligand gated ion channels change conformation?
binding/unbinding NT
What do Ionotropic receptors cause?
currents in postsynaptic neuron (PSC)
What determines the action of a transmitter?
type of receptor
Describe EPSP vs IPSP
EPSP = transient postsynaptic depolarization caused by presynaptic release of NT
IPSP = hyperpolarizing
What depolarizes a neuron to AP threshold in the first place?
EPSPs and (lack of) IPSPs
Describe Autoreceptors
-receptors commonly found in membrane of presynaptic axon terminal
-presynaptic receptors sensitive to the NT released by presynaptic terminal
-common effect is inhibition of NT release
-Negetive feedback system: can function as a safety valve if NT release is too high
Describe Exrasynaptic receptors
-receptors on postsynaptic neuron that sit on membrane, outside of synapse
-detect spillover, when transmitter becomes so concentrate as to escape synapse (synapse’s history)
-functions can differ from synaptic receptor
What is NMDA?
a receptor for NT glutamate
How can some NMDA receptors on one cell promote survival and others cell death?
Consequences depend on molecules nearby that communicate signals from receptors
Describe Metabotropic Receptors
-receptors signal through G-proteins, molecular “switches” that bind guanine (nucleotide) can have wide range of actions depending on which G-proteins and “effectors” are nearby
-not ion channels, but receptors that signal indirectly via molecular changes
-can signal nearby ion channels
-can use second messengers
What are second messengers?
molecules that diffuse from membrane and turn extracellular signal into intracellular signal
Compare ligand gated ion channel and G-protein -coupled receptors
one average, expect ligand gated ion channel t o be faster, but have shorter action than G-protein-coupled receptors
Describe GPCR (Gene-protein-coupled receptor) structure
-are part of a 7 trans-membrane domain superfamily
-coded by one, not multiple, genes
Describe GPCR family
-crosses membrane 7 times and activates G-protein
-1 gene per protein; thousands of genes
-most common pharmaceutical targets
What are ophan GPCRs
no ligand identified
What does the G-protein do in second messenger cascades?
couples NT with downstream enzyme activation
List the five steps for G-protein signaling
- Inactive: 3 subunits - alpha, beta, gamma- “float” in membrane (alpha bound to GDP)
- Active: bumps into activated receptor and exchanges GDP for GTP
- G(alpha) -GTP and G(beta gamma) - influence effector proteins
- G(alpha) inactivates by slowly converting GTP to GDP
- G(alpha) and G(BG) recombine to start the cycle again
Describe what happens in the G(as) metabotropic signaling cascade
-G-protein subunit alpha released upon NT binding
-Activates enzyme AC (adenylyl cyclase)
-AC produces cyclic AMP, second messenger
-cAMP binds and activates phosphorylating enzyme PKA (protein kinase A)
-Active PKA modifies CREB (cAMP response element binding protein), which binds DNA to alter gene expression
What do you get with G-protein couples receptors?
amplification
eg. many cAMP molecules
Describe what happens with increased cAMP vs. decreased cAMP
increased cAMP can lead to increased ~P which leads to closing of K+ channels- EXCITATORY
decreased cAMP can lead to decreased ~P which leads to opening of K+ channels - INHIBITORY
How can second messengers indirectly affect firing properties?
via ion channel modifications
What do kinases do?
phosphorylate proteins
What is key to NT function?
receptor location
Describe synaptic integration
-how neurons respond to combinations of synaptic inputs
-process by which multiple synaptic potentials combine within one post-synaptic neuron
-most neurons in brain and spinal cord receive thousands of synaptic inputs
-how neurons perform synaptic integration informs their computation
Describe the difference between spatial summation and temporal summation
spatial: multiple sites of activation
temporal: same synapse gets activated multiple times
What affects how synapses integrate?
proximity, shape of dendritic arbor influences integration
What do dendrites do to synaptic inputs?
compartmentalize
Describe neural coding
neurons represent information through their electrical activity
What influences the strength of downstream signaling?
spike rate
Describe rate code
information represented by the rate or frequency of action potentials of a neuron
Describe temporal code
information represented by the precise timing of action potentials of a neuron
The rate and timing of action potentials arise due to?
-synaptic input and integration
-neuron state
-electrical properties specific to the neuron (intrinsic properties)
What are intrinsic properties?
electrical properties that determine how a neuron activates and responds to input
Where do neurons get their diverse properties?
from distinct expression of ion channels
What happens in neurons that sustain activity?
allow brief events to trigger prolonged effects
Describe the differences in ion channels that allows for differences in ionic currents
-selectivity (potassium, sodium, calcium, chloride)
-gating- circumstances that cause the pore to open and close
-Kinetics - the speed of opening and closing
What are channelopathies?
diseases caused by defects in ion channels
What causes spike trains?
cycles of calcium, sodium and potassium channel activation
What is responsible for modifying rhythmic activity?
calcium
How doe calcium act?
similar to sodium, excitatory
What makes Calcium excellent for signaling action potentials?
almost absent from cytosol
What type of Calcium channels drive burst-firing?
T-Type
What does calcium accumulation cause?
inhibition via potassium channels
What are agonists of GABA(A) receptor called?
depressants
What are the different groups agonists that bind to GABA(A) Receptors?
ethanal, benzodiazepine (valium, librium, xanax), GABA, Barbiturate, Neurosteroids
What type of channel is the GABA(A) receptor?
gated Cl- channel
What does it mean to be a depressant?
tend to slow activity; tranquilizers, sedatives, hypnotics, anxiolytics (anti-anxiety)
