1: Synaptic Mechanisms Flashcards
Describe the basis for the concept of excitation versus inhibition with respect to synaptic transmission.
NT themselves are NEITHER excitatory nor inhibitory
—-The interaction of a given NT with a specific receptor determines inhibition versus excitation
Excitation: action of NT drives Vm toward a value that is MORE DEPOLARIZED than the threshold potential for generating an AP
Inhibition: action of NT KEEPS Vm from reaching threshold potential
List the fundamental steps in chemical transmission. (4)
- NT stored in presynaptic vesicles
- Depolarization -> open Ca channels -> Ca-dependent exocytosis
- Activation of postsynaptic receptors
- Termination
List three major excitatory ionotropic receptors and two major inhibitory ionotropic receptors.
Excitatory
- Nicotinic ACh receptors
- Glutamate receptors (NMDA, AMPA, Kainate)
- Purinergic receptors (adenosine, ATP)
Inhibitory
- GABA type A receptors
- Glycine receptors
Describe the difference between an ionotropic and metabotropic receptor, with specific reference to time course and specificity of action.
Ionotropic receptors: ligand-gated ion channels
- -Time course: msec
- -Specificity of action: allow ion to flow down its concentration gradient
Metabotropic receptors: GPCRs; promote activation of second messenger signaling pathways
- -Time course: msec to hours
- -Specificity of action: can have a multitude of effects on a range of second messenger systems
Describe the physical structures that allow electrical coupling between neurons or neurons and non-neuronal cells. Where are these common?
Gap junctions: specialized structures between cells that permit direct current flow and the passage of small ions that have signaling capabilities from one cell to the next
-Channel = connexon, build from 6 connexins
Common in developing tissue to allow coordinate development (-> cells function as a group)
-Also found in adult cochlea
What receptors are found at the neuromuscular junction?
Nicotinic AChR in the postsynaptic muscle cells
True/false: While a typical neuron in the CNS receives tens of thousands of inputs from a host of different presynaptic partners, a single muscle fiber is innervated by a single presynaptic axon (though each axon may contact more than one fiber [motor unit])
TRUE!
Describe the physical basis for mean quantal content and its importance in synaptic transmission.
M = n x p (m) = number of vesicles (n) x probability of vesicles being released (p)
Provides a critical mechanism by which synapses adjust their efficacy
- -Low in CNS -> basis for synaptic plasticity
- —Changes in m -> changes in plasticity -> adaptation to environment, optimized behavioral outputs
Define active zone. How do they function in response to APs?
On the presynaptic side, structures in which there are rows and rows of vesicles containing NT
-Located next to voltage-dependent calcium channels (VDCCs)
Depolarization -> rapid influx of Ca -> highly localized trigger for vesicle fusion and exocytosis of NT
What are postsynaptic specializations that maximize the safety factor and removal of ACh at the NMJ?
High densities of receptors are directly aligned with presynaptic active zones
-Surrounded by high densities of voltage-gated Na channels -> APs -> excitation-contraction coupling
Postsynaptic fold forms a funnel that directs free ACh down into it
-Has AChE to hydrolyze ACh for terminating its action
Describe “safety factor.” Where is it high and why? Where is it low and why?
Safety factor: the fidelity of transmission across a synapse
High at neuromuscular junction (1:1): each presynaptic AP gives rise to a postsynaptic AP
- Important because if you need to jump out of the way of a car, muscles need to respond
- High because of high mean quantal content and highly specialized organization that optimizes action of NT
Low at central synapses: need modulation and plasticity
- Single inputs by themselves can’t drive the system
- Need integration of many inputs to have information continue along a given pathway
What is the function of SNARES?
SNARES: located in synaptic vesicle membrane and in presynaptic terminal membrane
-Function in calcium-dependent vesicle fusion
Describe the molecular mechanism by which botulinum and tetanus toxins have their effects on neurotransmission.
Both work by proteolyzing SNARES -> blocking excocytosis
Botox: blocks synaptic transmission in motor neurons
Tetanus: retrogradely transmitted to inhibitory interneurons, which they inhibit (released inhibition of motor neurons -> activation)
**Describe the fundamental basis of reversal potential. How does it vary with development or disease?
The action of any NT acting at its ionotropic receptor will be to drive the membrane potential of the postsynaptic cell towards the reversal potential for that receptor.
Example: GABA receptor action changes during development
- Early in development - Cl transporter NKCC1 expressed -> [Cl]in is HIGH
- —GABA signaling -> depolarization -> EXCITATORY
- Later in development - Cl transporter KCC2 expressed -> [Cl]in is LOW
- —GABA signaling -> hyperpolarization -> INHIBITORY
Describe reversal potential in the context of the nicotinic ACh receptor. Is this receptor excitatory or inhibitory?
NAChR permeable to both Na AND K
-PNa is slightly > than Pk, so reversal potential is closer to that of Na, at 0 mV
Excitation because 0 mV is > than AP threshold (~45 mV)
Describe the pathology associated with the autoimmune disorders myasthenia gravis and Lambert-Eaton syndrome.
Myasthenia gravis: autoimmune disorder with antibodies against nicotinic AChR
- Results in insufficient NMJ transmission
- Decreases safety factor: APs in motor neuron do NOT always result in muscle fiber APs
Lambert-Eaton syndrome: an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels
How is Lambert-Eaton syndrome treated?
Treat with K channel blockers to allow more time for Ca to enter cell before it repolarizes
Disadvantage: takes longer between APs
What is succinylcholine chloride? How does it work?
Succinylcholine chloride: used as a muscle relaxant
-Competes with ACh for receptor binding/activation, resistant to cholinesterase degradation -> prolonged depolarization -> prevents repolarization -> muscle can’t contract
Describe the mechanism by which organophosphates can cause muscular paralysis.
Organophosphates: chemicals designed for use as pesiticides and as weapons which inactivate AChE
Result: high levels of ACh persist for abnormally long periods at the NMJ, -> desensitization -> insufficienct signaling -> cramping, weakness, respiratory failure
Describe how cholinesterases are used therapeutically to treat myasthenia gravis.
Anticholinesterases promote protracted residence of ACh in the synaptic cleft -> repeated AChR activation -> restoration of some synaptic efficacy
Describe the concept of subunit heterogeneity in the families of ligand-gated ion channels.
Different subunits are expressed/incorporated into functional receptors in a cell-, region-, and developmentally-specific way, resulting in…
- -Different allosteric modulator actions
- -Different desensitization
- -Different conductance
- -Different time receptor stays open
Give an example of where subunit heterogeneity is important in a normal neurobiological state or a disease.
EXAMPLE: infants less likely to die from rat poison (strychnine) than adults
- Neonates express an isoform of alpha subunit of glycine receptor with LOW strychnine binding affinity
- Adults -> HIGH strychnine binding affinity
What is allosteric modulation? What are some examples of allosteric modulators?
The ability of compounds to bind to sites on the GABA receptor and change the way the protein works when GABA binds and opens the channel
-Do NOT act as ligands, but alter the effects of GABA
Examples: ethanol, anesthetics, prednisolone, anabolic steroids
Describe presynaptic modulation. Give an example of how this process contributes to a fundamental neurobiological process, or where aberrant presynaptic modulation contributes to disease.
Presynaptic modulation: where inputs on the presynaptic terminal modulate NT release
EXAMPLE: NAChR receptors in CNS are predominantly on presynaptic nerve terminals
- -Activation of AChR -> depolarization of presynaptic terminal -> Ca entry through both AChR AND by opening Ca channels -> enhanced NT release
- -Nicotine -> increased presynaptic NT release from excitatory inputs, decreased NT release from inhibitory inputs -> enhanced dopaminergic activity
- —This is BECAUSE different kinds of AChR are present in the presynaptic terminals of excitatory and inhibitory inputs
- —–LONG-LASTING change in synaptic efficacy
Describe the differences in the functional properties of NMDA versus AMPA receptors.
AMPA:
- Heterotetramers
- Cation-selective (Na/K)
- Vrev = 0 mV (excitatory)
- Usually low Ca permeability
- Mediate fast synaptic excitation in nearly ALL CNS neurons
NMDA:
- Cation selective
- Vrev > 0 mV
- High Ca permeability
- Blocked by Mg at hyperpolarized and resting potentials
- Involved in long-term potentiation and depression
How is functional diversity in AMPA receptors generated? Give an example of where this goes wrong in a disease state.
Post-transcriptional mechanisms (alternative splicing, RNA editing)
ALS (some patients): defective editing of AMPA receptor subunits -> v. high Ca permeability -> Ca-dependent excitotoxicity
What can result from abnormal glutamate receptor function?
Excitotoxicity: implicated in TBI, ischemia, epilepsy, ALS, MS, Parkinson’s, Huntington’s, neuropathic pain syndromes
Describe the mechanisms in the CNS by which NT action is terminated. (3)
- Diffusion: simple diffusion can remove NT from the vicinity of cognate receptors
- Reuptake: most common mechanism to remove NT
- High affinity transporters expressed in presynaptic terminal and glial cells - Enzymatic degradation: as with AChE
- Often follows reuptake
Describe mechanisms by which presynaptic efficacy may be altered. (2)
Facilitation: increase mean quantal content by increasing probability of release via residual Ca
–Occurs if APs occur in rapid succession - not enough time for Ca to be cleared
Depression: decrease mean quantal content by decreasing number of releasable vesicles via high frequency of synaptic activity
- -Occurs with prolonged, high frequency synaptic activity
- -Progressively smaller synaptic responses
Describe mechanisms by which postsynaptic signaling may be altered. (3)
Temporal summation: two events arising in rapid succession from a single input may sum with each other
-Extend depends upon time constant of postsynaptic membrane
Spatial summation: two events arising from separate but adjacent inputs may sum with one another
-Extent depends upon length constant of postsynaptic membrane
Desensitization: after opening, if agonist is still present, conformation of protein changes so that even though ligand is bound, channel does not conduct ions
Describe the general mechanism by which metabotropic receptors signal. Consider second messenger heterogeneity, divergence of targets, and amplification.
Second messenger heterogeneity: one metabotropic receptor can activate many different downstream messengers
Amplification: at several steps, one molecule can give rise to many molecules
–Ex: binding of ligand to one receptor can activate many G proteins
Divergence: a given signaling molecule activated by a metabotropic receptor can alter the activity of several downstream targets
–Ex: phosphorylation of several different ion channels
