cellular neurobiology midterm 3

Define a Post-Synaptic Potential (PSP).

A voltage change in the postsynaptic cell that results from synaptic signaling.

What is the location and electrical nature of a PSP?

Occurs at the dendrite or soma. It is a graded potential (amplitude can be larger or smaller). It can be either depolarizing or hyperpolarizing.

What is the location and electrical nature of an Action Potential (AP)?

Occurs in the axon. It is all-or-nothing (each AP has the same amplitude

How do PSPs lead to Action Potentials?

A neuron fires when the sum of all PSPs (both excitatory and inhibitory) at the axon hillock reaches the threshold. Generally, one PSP from one synapse is not enough to cause firing

Anatomically, how do Electrical and Chemical Synapses differ?

Electrical: Pre- and post-synaptic cells are directly connected by gap junctions, sharing cytoplasm. Chemical: Cells do not touch, separated by a synaptic cleft (about 20 nm wide).

What are the key molecular components of an electrical synapse?

Connexins which form the gap junctions. Gap junctions are only selective by size.

What are the key electrophysiological properties of an electrical synapse?

The cells fire simultaneously (in synchrony). There is no synaptic delay.

What is a defining electrophysiological property of a chemical synapse?

Synaptic delay of about 0.5-1 ms due to neurotransmitter release. They allow for a variety of different effects in the postsynaptic cell.

Outline the 4 basic steps of synaptic transmission at a chemical synapse.

1. Depolarization opens voltage-gated calcium channels, and calcium enters the presynaptic terminal. 2. Calcium entry triggers exocytosis of vesicles. 3. Neurotransmitters diffuse across the cleft and bind to postsynaptic receptors. 4. Neurotransmitter signaling is ended by degradation or reuptake.

What protein acts as the calcium sensor to allow a vesicle to fuse with the axon membrane?

Synaptotagmin. When it binds calcium, it interacts with SNARE proteins to allow fusion.

How would lowering the amount of calcium in the extracellular fluid change the amplitude of the Postsynaptic Potential (EPP)?

Decrease its amplitude. Less calcium entry means fewer neurotransmitters are released, resulting in a smaller postsynaptic response.

What is the effect of Botulinum toxin (which cleaves the SNARE protein SNAP-25) on the EPP?

Decrease its amplitude (potentially to zero). SNARE proteins are necessary for the vesicle to fuse and release neurotransmitter.

Compare Clear-core vesicles and Dense-core vesicles on their appearance, content, and biogenesis location.

Clear-core: Small and hollow. Small molecule neurotransmitters. Synthesized and filled at the synapse. Dense-core: Large and dark. Neuropeptides (or biogenic amines). Synthesized and filled at the cell body (Golgi apparatus).

Which vesicle pool is released by a single action potential and requires less calcium?

The readily-releasable pool of clear-core vesicles, which are very close to the presynaptic membrane.

Which vesicles require a high-frequency train of electrical stimulation for release (more calcium)?

Clear-core vesicles from the reserve pool and Dense-core vesicles.

What is the function of Clathrin in vesicle recycling?

Clathrin triskelia attach to the vesicular membrane and coat the budding vesicle, physically forcing the membrane into a ball-like shape.

What is the function of Dynamin in vesicle recycling?

Dynamin forms a ring around the "neck" connecting the new vesicle to the plasma membrane and pinches it off.

What is the basic consequence of disrupting vesicle endocytosis?

It is more difficult and slower to make new vesicles, leading to fewer vesicles available for release

What is the "kiss-and-run" hypothesis?

The idea that vesicles can release their neurotransmitters by briefly opening a pore without fully fusing with the plasma membrane.

What is a quantum of neurotransmitter?

The amount of neurotransmitter contained in one vesicle. Since vesicles are roughly uniform, each quantum is a consistent size.

What is the consequence of the uniform size of vesicles on the postsynaptic response?

All postsynaptic voltage responses (e.g., EPPs) should be integer multiples of the voltage response to one vesicle.

How would a decrease in the amount of neurotransmitter loaded into each vesicle (a change in quantum size) affect the quantal release histogram?

It would shift the mV of the peaks (the peaks would be closer to 0 mV), but the responses would still have distinct peaks

What are the three ways neurotransmitter signaling is ended?

1. Diffusion away from the synapse. 2. Reuptake into the presynaptic terminal (or glia) OR Enzymatic Degradation. 3. Receptor Desensitization.

What is the effect of Sarin nerve gas, which inhibits acetylcholinesterase?

Acetylcholine (ACh) persists too long in the synaptic cleft, continuously activating ACh receptors and initially causing too much muscle contraction (paralysis)

Define receptor desensitization

When a neurotransmitter receptor stops passing current even though the neurotransmitter is still present.

How would a mutation that prevents receptor desensitization affect receptor signaling?

It would cause more receptor signaling, as desensitization normally reduces activity.

Distinguish between Ionotropic and Metabotropic receptors.

Ionotropic: Directly linked to an ion channel (ligand-gated ion channels). Fast effect (starts in 1-2 ms). Metabotropic: Affect neurons by activating G-proteins (G-protein-coupled receptors, GPCRs). Slow effect (can last minutes).

What ions flow through the Nicotinic Acetylcholine Receptor (nAChR), and what is the effect on a resting muscle cell?

Permeable to both Sodium and Potassium. At rest, the current is mainly due to Sodium influx, causing depolarization

What ions flow through Ionotropic Glutamate Receptors (GluRs), and what is the effect at rest?

ermeable to both Sodium and Potassium (some also Calcium). At rest, the current is mainly due to Sodium influx, causing depolarization.

What ion flows through the GABA-A receptor, and what is the effect in a mature neuron?

It is a Chloride channel. In a mature neuron, Chloride concentration is high outside the cell, so Chloride flows inward, causing hyperpolarization.

What is the general receptor type for Biogenic Amines and Neuropeptides?

Nearly all of their receptors are Metabotropic (GPCRs).

Ach synthesis enzyme 

choline acetyltransferase(ChAT)

Ach vesicle transporter

vesicular acetylcholine transporter(vAChT)

Ach cleft clearance mechanism

enzymatic degradation by acetylcholinesterase(AChE)

glutamate synthesis enzyme 

glutaminase 

glutamate vesicle transporter

vesicular glutamate transporter (VGLUT)

glutamate cleft clearance mechanism

reuptake by excitatory amino acid transporter(EAAT)

GABA synthesis enzyme 

GAD65 and GAD67 

GABA vesicular transporter

vesicular GABA transporter(VGAT)

GABA cleft clearance mechanism

reuptake by GABA transporters(GATs)

dopamine synthesis enzyme 

tyrosine hydroxylase, DOPA decarboxylase 

dopamine vesicle transporter

vesicular monoamine transporter(VMAT)

dopamine cleft clearance mechanism

reuptake(DAT) and degradation(MAO, COMT)

Compare Small Molecule and Neuropeptide neurotransmitters (synthesis/packaging).

Small Molecule: Small size. Synthesized by enzymes in the presynaptic terminal. Packaged into small, clear-core vesicles. Neuropeptide: Peptides (chains of amino acids). Synthesized by ribosomes in the cell body, packaged by Golgi apparatus. Packaged into large, dense-core vesicles.

How are neurons that release peptide neurotransmitters identified?

By staining (Immunohistochemistry, IHC) for the peptide itself or the mRNA of the peptide.

How are neurons that release small molecule neurotransmitters identified?

By staining for proteins involved in synthesizing, transporting, or clearing the neurotransmitter (since the NTs themselves are too small to stain).

Define a Retrograde Neurotransmitter and give an example.

A molecule that signals "backwards" from the postsynaptic cell to the presynaptic cell. Example: Endocannabinoids

GABA A receptors

ionotropic

cl-channel

GABA B receptors

metabotropic

indirect is to open K+ channel and block Ca 2+ channel

NKCC1

pumps na, cl, and k inside in immature neurons 

KCC2

pumps cl- and k outside in mature neurons 

What is the readily releasable pool?

Vesicles docked at membrane that release with a single AP.

What is the reserve pool?

Vesicles tethered further back; need high Ca²⁺ or bursts of stimulation to release.

What causes the disappearance of quantal peaks?

Vesicle size becomes variable OR receptor sensitivity becomes inconsistent.

nAChR type?

Ionotropic Na⁺/K⁺ cation channel.

mAChR type?

Metabotropic GPCR.

What is the reversal potential of nAChRs?

Approximately 0 mV.

Why is nAChR current depolarizing at rest?

At −90 mV, driving force is much stronger for Na⁺ influx than K⁺ efflux.
Thus Na⁺ inward current dominates → depolarization.

AMPAR ion permeability?

Na⁺ and K⁺ (sometimes Ca²⁺ depending on subunits).

NMDAR ion permeability?

Na⁺, K⁺, and always Ca²⁺.

What additionally gates NMDARs

Mg²⁺ block removed by depolarization.

Why does NMDAR require two conditions to open?

• Glutamate binding

• Sufficient depolarization to expel Mg²⁺
  This allows NMDARs to act as coincidence detectors for synaptic plasticity.

Which opens faster between AMPARs and NMDARs

NMDARs

What does APV block?

NMDARs only.

Why does NMDAR pass no current at −80 mV?

Mg²⁺ block cannot be removed at hyperpolarized potentials.

Why is GABA_A depolarizing in immature neurons?

Immature neurons have high intracellular Cl⁻ due to NKCC1 activity → Cl⁻ flows OUT when channel opens → depolarizes cell.

Why is GABA_A hyperpolarizing in adults?

KCC2 pumps Cl⁻ out → low intracellular Cl⁻ → Cl⁻ flows IN when channel opens → hyperpolarization.

What determines whether a receptor’s PSP is excitatory or inhibitory?

The reversal potential relative to threshold.

When is a PSP excitatory?

Erev > threshold.

When is a PSP inhibitory?

Erev < threshold.

Can a depolarizing PSP be inhibitory?

Yes—if its reversal potential is below threshold.

What is an EPSC?

An inward (negative) postsynaptic current.

What is an IPSC?

An outward (positive) postsynaptic current.

What is spatial summation?

Combining inputs from different synapses across dendrites.

Which synapse has more influence—proximal or distal?

Proximal, because PSPs attenuate over distance.

What is temporal summation?

Multiple PSPs from the same synapse arriving close in time summate.

How does diazepam affect summation?

Diazepam increases GABA_A channel open time → IPSPs last longer → easier temporal summation → stronger inhibition

Why didn’t changing Cl⁻ shift nAChR reversal potential?

nAChRs are not permeable to Cl⁻ → no effect on Erev.

Why can NMDAR current only occur when depolarized?

Mg²⁺ blocks pore at negative voltages; depolarization repels Mg²⁺.

Why does AMPAR current exist at −80 mV but NMDAR current does not?

AMPARs have no Mg²⁺ block → can pass Na⁺ at any voltage.
NMDARs remain Mg²⁺-blocked at −80 mV.

Why does increasing KCC2 expression strengthen inhibition?

Lower intracellular Cl⁻ → larger hyperpolarizing Cl⁻ influx when GABA_A opens.

What happens if KCC2 is downregulated in adults? (

Intracellular Cl⁻ rises → GABA_A becomes less hyperpolarizing or even depolarizing → increased excitability → can cause seizures.

What causes excitotoxicity?

Prolonged activation of NMDARs → massive Ca²⁺ influx → activation of proteases, mitochondrial failure → neuronal death.
Occurs in stroke, hypoglycemia, trauma.

How is GABA synthesized?

GAD65/67 convert glutamate → GABA.

What loads GABA into vesicles?

VGAT

How is GABA cleared?

GAT (GABA transporters).

Why are GABAergic neurons often interneurons?

They provide fast, local inhibition to sculpt network activity.

What does increasing extracellular Ca²⁺ do?

Raises release probability → larger PSPs.

What effect does decreasing extracellular Ca²⁺ have on NMJ?

Weak endplate potentials → failed muscle contraction.

What does receptor upregulation do?

Increases postsynaptic sensitivity.

What does receptor downregulation do?

Decreases postsynaptic sensitivity → smaller PSPs.

What is a neuromodulator neurotransmitter?

a neurotransmitter that modulates neuron behavior indirectly by altering intracellular signaling (enzyme activity, channel opening/closing, gene expression) rather than directly causing ion flow via ionotropic receptors.

How do neuromodulators change firing without ionotropic receptors?

They alter firing indirectly by triggering intracellular cascades that open/close channels, activate enzymes, or change gene expression.

What is reception in cell signaling?

Reception is when a ligand binds to a specific receptor, initiating signal detection.

Which phase of signaling always directly interacts with a chemical signal?

Reception, because it requires direct ligand–receptor binding.

What is signal transduction?

The intracellular cascade of molecular events triggered by receptor activation, leading to cellular changes.

What is the “response” in cell signaling?

The final cellular effect—such as activating enzymes, changing shape, modifying gene expression, or altering membrane channels.

What does GPCR stand for, and what does it do?

GPCR = G-protein-coupled receptor; it activates a G-protein when its ligand binds.

What are the two types of G-proteins?

• Heterotrimeric G-proteins (α, β, γ subunits)

  • Monomeric small G-proteins (e.g., Ras, Rho)

What nucleotide states do G-proteins bind?

They bind GDP (inactive) and GTP (active).