N371: Synaptic Transmission + Plasticity

What’s the difference between learning and memory?

1. = process of acquiring new information

2. = persistence of that information, retrievable later

What’s memory consolidation?

The stabilization of memories after formation (short-term → long-term)
→ Concept introduced by Müller & Pilzecker, 1900

What are William James’ stages of memory?

1. After-image trace: brief sensory impression

2. Primary memory: short-term, active, fades quickly

3. Secondary memory: long-term, inactive but retrievable

What did Santiago Ramón y Cajal propose?

• Neuron Doctrine: brain = discrete, individual neurons

• Synaptic Plasticity Hypothesis: synaptic strength can change with experience

What did Donald Hebb contribute?

The concept of cell assemblies — neurons that fire together form stronger connections (“cells that fire together wire together”).

Explain Hebb’s grass path analogy.

Walk once = no change; walk repeatedly = flattened path → easier to follow → stronger connection.

What does activity-dependent plasticity mean?

Synaptic strength changes based on patterns of neural activity — foundation of learning and memory.

What is the Aplysia gill-withdrawal reflex?

A defensive reflex: touching the siphon/body causes gill retraction.
→ Can be modified by experience = model for learning.

What types of learning does Aplysia show?

Habituation, sensitization, and classical conditioning.

What happens during habituation?

Non associative learning.The gill-withdrawal response weakens with repeated harmless stimulation.

Mechanism of habituation?

Homosynaptic depression

What is homosynaptic depression?

Changes occur at the same synapse that was repeatedly active.

What is Heterosynaptic plasticity?

Changes are induced by a different neuron’s modulatory input acting on the synapse.

Cellular/anatomical changes as a result of habituation?

presynaptic changes: less vesicle release per AP + less Ca2+ less vescile docking at active zone

anatomical changes: fewer physical synapses between sensory/motor neurons

overall result = fewer EPSP in motor neuron

What happens during sensitization?

The gill-withdrawal reflex enhances after a strong/noxious stimulus

Where does the modification begin during sensitization?

axo-axonic synapse — a facilitating interneuron synapses on the sensory neuron's axon terminal.

Mechanism of sensitization?

Heterosynaptic

Neurotransmitter and receptor involved in habituation?

Tail shock = serotonin (5-HT) released from the facilitating interneuron → binds to metabotropic 5-HT receptors on the sensory neuron —> signalling cascase 

Signaling cascade for short-term sensitization?

5-HT → Gs protein → Adenylyl cyclase → ↑ cAMP → activates PKA + PKC

Cellular short term effects of sensitization?

phosphorylation(inactivation) of K+ channels + more Ca2+ entry + mobilization of vesicles. overall result = larger EPSP in motor neuron

What triggers long-term changes in sensitization?

Prolonged or repeated 5-HT stimulation → sustained cAMP/PKA activation.

What happens in the nucleus during long term sensitization?

• PKA catalytic subunits enter nucleus → activate CREB (cAMP Response Element-Binding protein).

• CREB binds CRE sites on DNA → turns on genes.

What genes are activated by CREB/CRE?

• Ubiquitin hydrolase → maintains persistent PKA activity

• Protein synthesis genes → for structural changes (like new synapses)
  → Leads to long-term facilitation (L-LTP).

What is the basic setup of classical conditioning in Aplysia?

Pairing a weak siphon tap (CS) with a tail shock (US) → gill withdrawal response to the tap alone.

What’s the key mechanism of classical conditioning?

Tail shock = serotonin (5-HT) released from the facilitating interneuron BUT ALSO sensory neuron active at the same time (5HT signal arrives when sensory is already depolarized) = moer caMP = more PKA = more NT release 

Next, during light tap = stronger EPSP since sensory neuron now releases more NT

Why is this classical conditioning associative?

The strengthening only occurs when presynaptic and modulatory signals coincide.
→ “Timing matters”: tap + tail shock = learning; tap alone = no change.

Who discovered Long-Term Potentiation (LTP)?

Bliss & Lømo — they stimulated the perforant path in the dentate gyrus of the hippocampus.

What is Long-Term Potentiation (LTP)?

An enduring increase in synaptic strength that occurs after strong stimulation. After a strong stimulus, later weak stimuli produce larger responses than before — showing synaptic strengthening.

What are the three main components of the hippocampal trisynaptic circuit?

• Perforant Path: entorhinal cortex → dentate gyrus (granule cells)

• Mossy Fibers: axons of granule cells → CA3 pyramidal neurons

• Schaffer Collaterals: axon collaterals of CA3 → CA1 pyramidal neurons

What is the function of the perforant path?

It funnels cortical input into the hippocampus for processing and storage.

What are mossy fibers in the hippocampus?

Axons of dentate gyrus granule cells that project to CA3 pyramidal neurons.

What are NMDA receptors and why are they called coincidence detectors?

They detect when both presynaptic and postsynaptic neurons are active simultaneously.
They require (1) glutamate + glycine binding (presynaptic signal) and (2) strong depolarization (postsynaptic signal to remove Mg²⁺ block).

What event removes the Mg²⁺ block from NMDA receptors?

Strong postsynaptic depolarization, allowing Ca²⁺ influx.

What is short-term LTP (S-LTP)?

A fast, transient enhancement lasting seconds to minutes; depends on post-translational modifications like phosphorylation — no new protein synthesis needed.

What is long-term LTP (L-LTP)?

A stable, long-lasting strengthening (hours–days–weeks) that requires gene transcription, protein synthesis, and structural remodeling (growth of new spines/synapses).

Which transcription factor is key for long-term LTP?

CREB (cAMP Response Element–Binding Protein) — activated to initiate new gene expression.

How is long-term LTP structurally expressed in neurons?

Through growth of new dendritic spines and formation of new synapses.

What does the “Co-operativity” rule of LTP mean?

Several presynaptic inputs must fire together to sufficiently depolarize the postsynaptic cell and remove the NMDA Mg²⁺ block — ensures only strong patterns are stored.

What does the “Associativity” rule of LTP mean?

A weak input can be strengthened if active simultaneously with a strong input on the same postsynaptic neuron — reflects Hebb’s rule

What does the “Specificity” rule of LTP mean?

LTP occurs only at active synapses that received stimulation; inactive neighboring synapses remain unchanged — allows pathway-specific learning.

Is Long-Term Potentiation (LTP) the same as memory?

Not exactly — LTP is the best-established model for how experience strengthens synapses, forming the biological foundation of memory.

What behavioral evidence links LTP to learning?

Learning tasks (e.g., Morris water maze) cause LTP-like synaptic strengthening in the hippocampus.

What experimental manipulations show causality between LTP and memory?

• Blocking LTP (pharmacologically/genetically) → impairs memory formation.

• Inducing LTP artificially → enhances learning or creates “memory-like” traces.

What is synaptic transmission?

The process of communication between neurons, where a presynaptic neuron influences a postsynaptic cell via electrical or chemical signals.

Who introduced the term synapse?

Charles Sherrington, who defined it as the specialized zone of contact between neurons.

Who first visualized the structure of synapses?

Santiago Ramón y Cajal, using Golgi staining.

What are the three structural parts of a synapse?

• Presynaptic terminal: axon terminal that releases the signal

• Synaptic cleft (zone of apposition): gap where neurotransmitters diffuse

• Postsynaptic target: receptor region on the receiving cell

What is the zone of apposition?

The small gap (synaptic cleft) between pre- and postsynaptic membranes where communication occurs.

What are the two main types of synapses?

Electrical and chemical synapses — defined by how signals pass from one neuron to another.

How do electrical synapses transmit signals?

Through direct, passive flow of current via gap junctions connecting the cytoplasms of adjacent cells.

What are gap junctions made of?

Connexons, each formed by six connexin subunits; two connexons (one from each cell) align to form a continuous pore.

What are the main advantages of electrical synapses?

• Speed: almost instantaneous transmission

• Synchronization: neurons fire together

• Bidirectionality: current can flow both ways, promoting coupling

How do chemical synapses transmit information?

The presynaptic neuron releases neurotransmitters into the synaptic cleft, which bind to receptors on the postsynaptic membrane.

What is the active zone?

The area in the presynaptic terminal where synaptic vesicles fuse and release neurotransmitters.

What is the postsynaptic density (PSD)?

A dense region on the postsynaptic side rich in receptors and scaffolding proteins, crucial for signal detection and transduction (especially at excitatory synapses).

What are the two major categories of neurotransmitters?

• Small-molecule neurotransmitters: fast, short-acting (in small clear-core vesicles)

• Neuropeptides: slow, long-lasting (in large dense-core vesicles)

Where are small-molecule NTs synthesized?

Locally in the presynaptic terminal.

Where are neuropeptides synthesized?

In the soma, then transported down the axon to terminals.

What does “co-transmission” mean?

A single neuron can release more than one neurotransmitter, depending on firing pattern or activity intensity.

Can one postsynaptic neuron receive both excitatory and inhibitory signals?

Yes — a postsynaptic neuron can be excited by one NT and inhibited by another.

What does quantal release mean?

Neurotransmitters are released in discrete packets (quanta), each representing the contents of one vesicle.

What is an end-plate potential (EPP)?

The depolarization of a muscle fiber caused by ACh release at the neuromuscular junction — large enough to trigger contraction when summed.

What is a miniature end-plate potential (MEPP)?

A small, spontaneous depolarization caused by the random release of a single vesicle — one quantum — not enough to trigger an AP alone.

What evidence supports the quantal theory of release?

• Blocking EPPs also blocks MEPPs → same transmitter involved.

• Lowering external Ca²⁺ reduces EPP size in step-like quantal increments, showing each EPP = sum of multiple MEPPs.

What happens to synaptic vesicles after exocytosis?

The presynaptic membrane area temporarily increases, then vesicles are retrieved by endocytosis and recycled to maintain terminal stability and readiness for the next signal.

Why is vesicle recycling important?

It prevents unchecked membrane growth and ensures vesicle availability for continuous neurotransmission.

What ion is both necessary and sufficient for neurotransmitter release?

Ca2+

What experimental evidence shows Ca²⁺ is necessary for neurotransmitter release?

• Blocking Ca²⁺ channels prevents NT release.

• Injecting Ca²⁺ chelators (which bind Ca²⁺) blocks release.

• Injecting Ca2+ into presynaptic can trigger release without AP

• Blocking Na+ channels with TTX does not stop release as long as Ca2+ is available

What is the function of synapsin in vesicle cycling?

Synapsin tethers vesicles together into a reserve pool within the presynaptic terminal.

How are vesicles released from the reserve pool?

CaMKII phosphorylates synapsin, freeing vesicles so they can move toward the active zone.

What happens during the docking step of vesicle release?

Vesicles physically attach to the presynaptic active zone using SNARE proteins and accessory anchoring proteins.

What is vesicle priming?

A preparatory stage where the SNARE complex forms between vesicle and membrane proteins, positioning the vesicle close to Ca²⁺ channels and making it “fusion ready.”

What triggers synaptic vesicle fusion?

Ca²⁺ binds to synaptotagmin, a Ca²⁺ sensor protein on the vesicle, which activates the SNARE complex and causes membrane fusion (exocytosis).

What protein serves as the Ca²⁺ sensor for neurotransmitter release?

Synaptotagmin

How is the vesicle membrane retrieved after neurotransmitter release?

By clathrin-mediated endocytosis.

What protein coats the budding vesicle during endocytosis?

Clathrin, which forms a lattice structure around the vesicle.

What adaptor connects clathrin to vesicle proteins and receptors?

Adaptor protein complex AP-2.

What enzyme pinches off the vesicle from the membrane?

Dynamin, a GTPase that constricts the vesicle neck.

What removes the clathrin coat after vesicle internalization?

Hsc70 and auxilin — they uncoat the vesicle for reuse.

What are the two fates of a recycled vesicle?

• Refilled with neurotransmitter via vesicular transporters

• Fused with an endosome for further processing

What determines if a neuron will fire an action potential?

The total summation of all EPSPs and IPSPs — if the combined depolarization reaches threshold.

What is spatial summation?

When multiple synapses on different dendritic sites are active at the same time, their PSPs add together.

What is temporal summation?

When rapid successive inputs occur at the same synapse, their PSPs stack in time to produce a larger effect.

Why must PSPs occur close in time to summate effectively?

Because PSPs decay quickly; if inputs are too far apart in time, their effects don’t overlap enough to reach threshold.