Synaptic Plasticity and Memory

Question 1

Aplysia Gill Withdrawal Relfex Circuitry (Sensitization)

Answer 1

1. Activation of the facilitatory pathway
   - A noxious stimulus activated the tail sensory neuron
   - Tail sensory neuron (glutamatergic) excites the modulatory (facilitatory) interneuron
   - This interneuron is serotonergic and forms an axo-axonic synapse onto the sensory neuron’s axon terminal
2. Serotonin receptor activation
   - The facilitatory interneuron releases serotonin
   - Serotonin binds to a metabotropic serotonin receptor on the presynaptic terminal of the sensory neuron
   - This receptor is a G-protein–coupled receptor
3. G-protein and adenylyl cyclase signaling
   - Activation of the G-protein stimulates adenylyl cyclase
   - Adenylyl cyclase converts ATP → cAMP
   (this is the ATP release/usage step)
   Result: Intracellular cAMP levels increase
4. Activation of protein kinase A (PKA)
   - cAMP binds to the regulatory subunits of protein kinase A
   - This causes the catalytic subunits of PKA to dissociate and become active
5. Ion channel modulation in the sensory neuron
   Active PKA catalytic subunits phosphorylate (adds PO4) ion channels:
   K⁺ channel
   - K⁺ channels are closed
   - Action potential duration is prolonged
   Ca²⁺ channel
   - Prolonged depolarization causes Ca²⁺ channels to remain open longer
   - Ca²⁺ influx increases
6. Increased neurotransmitter release
   Increased Ca²⁺ in the sensory neuron terminal causes:
   - ↑ vesicle fusion
   - ↑ glutamate release
7. Enhanced motor neuron response
   - Glutamate binds to glutamate receptors on the motor neuron
   - Motor neuron firing increases
   - Gill withdrawal becomes stronger and longer-lasting

Question 2

Habituation

Answer 2

A progressive decrease in response to a repeated stimulus
- Keep responding = waste of energy

Question 3

Sensitization

Answer 3

A heightened response to an innocuous stimulus, caused by a previous noxious stimulus

Question 4

Tetanus

Answer 4

High frequency (~100 Hz) Stimulation

Question 5

LTP Specificity

Answer 5

Only the synapses that are active during induction of LTP become strengthened; inactive neighboring synapses on the same neuron do not
- Specificity ensures that only the synaptic connections carrying meaningful information are modified

LTP specificity refers to the strengthening of only those synapses that are active during induction, because NMDA receptor–mediated Ca²⁺ influx occurs only at synapses experiencing simultaneous presynaptic glutamate release and postsynaptic depolarization.

1. Presynaptic activity is synapse-specific
   - An active presynaptic terminal releases glutamate
   - Inactive synapses release no glutamate
2. Postsynaptic depolarization is local
   - Glutamate binds AMPA receptors
   - Na⁺ influx depolarizes the postsynaptic spine
   - This depolarization is restricted to that spine
3. NMDA receptors act as a coincidence detector
   NMDA receptors require:
   - Glutamate binding (presynaptic activity)
   - Postsynaptic depolarization (to remove Mg²⁺ block)
   (Only synapses that satisfy both conditions activate NMDA receptors)
4. Local Ca²⁺ influx
   - NMDA receptor opening allows Ca²⁺ entry
   - Ca²⁺ is confined to the activated spine
   - Neighboring spines do not experience this Ca²⁺ signal
5. Synapse-specific strengthening
   - Ca²⁺ activates kinases (e.g., CaMKII)
   Leads to:
   - Increased AMPA receptor conductance
   - Insertion of additional AMPA receptors
   - Only the active synapse is potentiated

Only stimulated synapses have glutamate + depolarization → Ca²⁺ entry

Question 6

Associativity LTP

Answer 6

A weak input can undergo LTP if it is active at the same time as a strong input onto the same postsynaptic neuron
(A single pairing or a few pairings induces LTP)
TP associativity occurs when a weak synapse is potentiated because it is co-active with a strong synapse that provides sufficient postsynaptic depolarization to relieve the NMDA receptor Mg²⁺ block

1. Strong pathway activated
   - Releases glutamate
   - Produces large postsynaptic depolarization via AMPA receptors
2. Weak pathway activated simultaneously
   - Releases glutamate
   - On its own, would not depolarize the neuron enough
3. Shared postsynaptic depolarization
   - The strong input depolarizes the postsynaptic membrane
   - This removes the Mg²⁺ block from NMDA receptors at both synapses
4. NMDA receptor coincidence detection
   Weak synapse:
   - Has glutamate bound
   - Experiences depolarization from the strong synapse
   NMDA receptors open
5. Ca²⁺ influx at the weak synapse
   - Triggers intracellular signaling
   - Weak synapse becomes potentiated

Question 7

Cooperativity LTP

Answer 7

Multiple weak inputs can collectively induce LTP if they are activated simultaneously
(Many repetitions are required to obtain LTP)
LTP cooperativity occurs when simultaneous activation of multiple weak synapses produces sufficient postsynaptic depolarization to activate NMDA receptors and induce synaptic strengthening

1. Several weak synapses activated together
   - Each releases glutamate
   - Each produces a small depolarization
2. Summation of depolarization
   - Spatial summation of EPSPs
   - Postsynaptic depolarization becomes large enough
3. NMDA receptor activation
   - Mg²⁺ block is removed at active synapses
   - Glutamate is present
4. Ca²⁺ influx
   - Ca²⁺ enters through NMDA receptors
   - Triggers LTP signaling pathways
5. Potentiation of all active synapses
   - All co-active synapses are strengthened

Question 8

Dendritic Spines

Answer 8

Dendritic spines are the primary postsynaptic sites of glutamatergic excitatory synapses, containing AMPA and NMDA receptors, and support synapse-specific plasticity such as LTP

Question 9

NMDA Receptor

Answer 9

NMDA receptors act as coincidence detectors, requiring both presynaptic glutamate release and postsynaptic depolarization to open

At resting potential:
- Presynaptic neuron releases glutamate
- Glutamate binds to the NMDA receptor
- Channel does NOT conduct ions

NMDA receptor pore is blocked by Mg²⁺
Postsynaptic membrane is hyperpolarized (≈ −70 mV)
Mg²⁺ remains lodged in the channel due to electrostatic attraction

During postsynaptic depolarization
- High-frequency stimulation releases large amounts of glutamate
- Glutamate activates AMPA receptors
- Na⁺ influx through AMPA receptors depolarizes the postsynaptic membrane

Depolarization repels Mg²⁺ from the NMDA channel pore
Mg²⁺ block is removed

NMDA receptor channel opens
Conditions now met:
1. Glutamate is bound
2. Mg²⁺ block removed

Ion flow through NMDA receptor:
- Ca²⁺ enters (most important, initiates LTP)
- Na⁺ enters
- K⁺ exits

Localized Ca²⁺ influx triggers LTP

Question 10

NMDA Receptors Summary

Answer 10

At resting potential or during weak synaptic stimulation, glutamate released from the presynaptic neuron binds primarily to AMPA receptors, producing a small Na⁺ influx and a modest depolarization of the dendritic spine. This depolarization is insufficient to expel the Mg²⁺ ion from the NMDA receptor channel, so NMDA receptors remain blocked and Ca²⁺ does not enter the postsynaptic neuron. Because Ca²⁺ influx through NMDA receptors is required to trigger intracellular signaling cascades, LTP is not initiated

Question 11

Compare 3 Types of LTP

Answer 11

Specificity:
Only stimulated synapses have glutamate + depolarization → Ca²⁺ entry

Cooperative:
Each axon releases glutamate at its own synapse
EPSP produces strong postsynaptic depolarization

Associative:
Glutamate is releases at both the strong and weak synapse
Strong synapse - Produces large depolarization (spread along the dendrite)
Weak synapse - Receives depolarization

Question 12

LTP Expression

Answer 12

How the synapse actually becomes stronger after LTP has been induced
Mechanisms by which synaptic transmission is persistently enhanced following LTP induction
Implements learning-related changes
“The stored trace (what makes the memory usable later)”

Question 13

Long-Term Potentiation

Answer 13

Persistent increase in synaptic efficacy that follows high-frequency or correlated activation of presynaptic and postsynaptic neurons

Question 14

LTP Induction

Answer 14

Triggers learning related change
“Learning signal”

Question 15

Mechanisms for LTP Expression

Answer 15

1. Enhancement of existing AMPA receptor conductance
   (AMPA receptors already present in the synapse become more effective)
   Mechanism:
2. Ca²⁺ enters the dendritic spine through NMDA receptors
3. Ca²⁺ activates intracellular Ca++ calmodulin kinase II
4. These kinases phosphorylate AMPA receptor subunits

Increased single-channel conductance
Increased open probability
AMPA receptors pass more Na⁺ per glutamate binding
(Same amount of glutamate → larger EPSP)
Important in early LTP

2. Insertion of new AMPA receptors
   (More AMPA receptors are added to the synapse)
   Mechanism:
3. NMDA-mediated Ca²⁺ influx activates CaMKII
4. CaMKII triggers:
   - Mobilization of AMPA receptors from intracellular vesicles
   - Exocytosis into the postsynaptic membrane
5. AMPA receptors are:
   - Inserted extrasynaptically
   - Then trapped at the synapse by scaffolding proteins

Question 16

Declarative Memory

Answer 16

Available to consciousness
Explicit

Question 17

Nondeclarative Memory

Answer 17

Generally not available to consciousness
Implicit

Question 18

Retrograde Amnesia

Answer 18

Loss of previously strored memories

Question 19

Anterograde Amnesia

Answer 19

Inability to form new memories

Question 20

Hippocampus

Answer 20

Involved in:
- Consolidation of new explicit, long-term memories

Not involved in:
- Long-term storage of explicit memories
- Consolidation or storage of implicit memories

Hippocampus = “Librarian”
Cerebral Cortex = “Library”

Question 21

H.M.

Answer 21

Suffered from intractable epilepssy
Has bilateral hippocampectomy

Did not remember meeting people just minutes earlier
Temporally graded retrograde amnesia: Lost memory of some events in the decade preceding surgery, older memories from earlier life were intact
Could acquire new implicit memories, and had normal working memory

Question 22

Explicit Memory Consolidation and Storage Model

Answer 22

Overall:
1. The Hippocampus rapidly binds features of an experience.
2. The Neocortex gradually stores long-term associations.
3. Over time, cortico-cortical synapses strengthen, and hippocampal involvement becomes less necessary

Process
1. Initial encoding in the hippocampus
- Sight and smell activate different cortical inputs
- These converge onto the same hippocampal neuron
Simultaneous activation produces:
- Strong depolarization
- NMDA activation
Cooperative LTP at hippocampal synapses

2. Early hippocampo–cortical interactions
   - Early on, cortical synapses (C and D) are weak
   Hippocampal activation during recall or replay:
   - Drives coordinated cortical activity
   - Allows associative LTP in cortex
   This usually occurs during:
   - Repeated recall
   - Sleep
   - Offline replay
   Cortical associative LTP depends on hippocampal-driven coactivation, not just casual exposure
3. Long-term consolidation via hippocampal replay
   - Hippocampus reactivates cortical patterns
   Repeated coactivation:
   - Strengthens direct cortico-cortical connections
   - Uses associative LTP
   Eventually:
   Sight ↔ smell become linked without hippocampus
4. Long-term cortical storage & hippocampal reuse
   - Memory is now stored in distributed cortical synapses
   Hippocampal synapses:
   - Become less critical
   - May weaken or remodel
   The hippocampus:
   - Is not erased
   - But is freed from dependence on that memory

The hippocampus is reusable because:
- Cortical networks now sustain the memory
- Hippocampal plasticity is ongoing and flexible