Synaptic Plasticity, Learning, and Memory

Synaptic Plasticity

Synaptic plasticity refers to the ability of synapses in certain brain areas (e.g., olfactory cortex, hippocampus) to have their strength modified by their own activity.
Plasticity results from molecular and structural changes within the synapse.
Key forms of synaptic plasticity:
- Long-Term Potentiation (LTP)
- Long-Term Depression (LTD)

Forms of Synaptic Plasticity

Long-Term Potentiation (LTP):
- Strengthens excitatory synapses through an increase in activity.
- Crucial for learning and memory processes.
Long-Term Depression (LTD):
- Activity-dependent decrease in the efficacy of synapses.
LTP and LTD are outcomes of cellular mechanisms used by various neuronal networks.

Ways to Study Plasticity

Experimental approaches to clinical issues related to the cerebral cortex in neurodegenerative and psychiatric disorders are used to study plasticity.

LTP in the Hippocampus

LTP is a significant form of plasticity in the nervous system.
The hippocampus is a key area for LTP study, specifically the Schaffer collaterals (from CA3 pyramidal neurons) synapsing onto CA1 pyramidal neurons.
These synapses are glutamatergic and excitatory.
The synaptic network in the hippocampus is well-defined and relatively simple.

Hippocampus

The term "hippocampus" originates from Greek, with "hippo" meaning horse and "campus" referring to a sea monster or seahorse, due to its resemblance to a seahorse.
Located in the medial region of the temporal lobe.
It is a component of the Limbic System, which is involved in emotions and memory.
Plays an important role in learning and memory.

Recordings From Hippocampal Slices

LTP is extensively studied using hippocampal brain slices.
Schaffer collaterals (SC) are processes from CA3 pyramidal neurons that synapse onto CA1 neurons.

Hippocampal Connectivity

EC (Entorhinal Cortex):
- Major input to the hippocampus.
- Receives inputs from temporal, orbital, and olfactory cortices, as well as the amygdala.
- Outputs primarily to the amygdala and nucleus accumbens, and also to cortical areas.
DG (Dentate Gyrus)
Sub (Subiculum)

Long-Term Potentiation (LTP) Characteristics

Strong, repetitive stimulation of synapses can induce and maintain LTP.
Hippocampal plasticity requires simultaneous activation of both pre- and post-synaptic components.
Hippocampal plasticity is NMDAR-dependent. Plasticity in other brain areas is also NMDAR-dependent.
Increased post-synaptic responses are structurally based (e.g., formation of additional postsynaptic sites) and molecularly based (protein synthesis, signaling).

NMDARs as Coincidence Sensors

NMDARs (N-methyl-D-aspartate receptors) act as coincidence detectors requiring two events for activation:
- Glutamate binding to NMDARs.
- Sufficient depolarization of the cell membrane to expel $Mg^{2+}$ ions that block the NMDAR pore under normal conditions.
NMDARs are permeable to $Ca^{2+}$ ions.

NMDAR-mediated LTP in Hippocampus

Recordings from mutant mice lacking NMDARs in the CA1 region show impairments in LTP induction.
Mutant mice exhibit slower learning in tasks like finding a submerged platform.

Experimental Induction of LTP

Under experimental conditions, LTP can be induced via a tetanus.
- Tetanus: a brief burst of high-frequency stimulation.
- Example: 50-100 stimuli at 100/s delivered to Schaffer collaterals.
Baseline excitatory post-synaptic potentials (EPSPs) are established with test stimulation: slow and over a longer period of time – one per minute for 15-30 minutes.
LTP can be induced by stimulation lasting less than a second and within physiologically relevant firing frequencies.

Steps for LTP Induction

Excitation in the presynaptic neuron leads to the release of glutamate.
Glutamate binds to postsynaptic AMPA receptors.
$Na^+$ ions flow into the postsynapse via glutamate-activated AMPA receptors.
Postsynaptic membrane depolarizes, but this depolarization may initially be below the threshold required for the expulsion of $Mg^{2+}$ ions from NMDARs.
If the postsynaptic membrane depolarizes sufficiently:
- $Mg^{2+}$ ions are expelled from NMDARs.
- NMDARs open, allowing $Ca^{2+}$ ions to enter.

Early and Late Phases of LTP

Early Phase:
- Involves the insertion of more AMPA receptors into the postsynaptic membrane.
- Does not require new protein synthesis.
- Short-lasting, from one to a few hours.
Late Phase:
- Requires additional signaling pathways.
- Involves the synthesis of new proteins and RNA.
- Long-lasting, at least 24 hours.

Role of Calcium in LTP

Opening of NMDARs leads to $Ca^{2+}$ influx.
$Ca^{2+}$ concentration rises inside the postsynapse.
$Ca^{2+}$ activates protein kinase C (PKC) and calcium-calmodulin-dependent protein kinase II (CaMKII).
Inhibition of $Ca^{2+}$ increases or the activation of these kinases inhibits LTP induction.

Molecular Pathways in LTP

Following $Ca^{2+}$ increases and kinase activation:
- AMPA receptors can be phosphorylated, enhancing their activity and leading to an enhanced postsynaptic response.
- Vesicles carrying AMPA receptors can fuse with the membrane, increasing the number of receptors and enhancing the synaptic response.

Structural Changes in LTP

Dendritic spine morphogenesis occurs following LTP induction (late LTP).
This involves activity-dependent formation, growth, and maturation of new spines.
Leads to increased connectivity between axons and dendrites, more contacts, a larger overall contact area, and an increased probability of synaptic release.

Input Specificity of LTP

Only synapses receiving strong inputs are strengthened.
Not all synaptic connections are strengthened.
Important for learning and memory.
Allows differentiation between signals.
Example: If Schaffer collaterals making synaptic connections on the left side of a CA1 neuron's dendrites receive strong (tetanic) stimulation, while those on the right receive weak stimulation, only the synapses on the left will undergo LTP.

LTD – Long-Term Depression

Synapses are plastic and can be modified to become depressed or weakened (LTD).
This bidirectional modification can occur in the same location and is activity-dependent.
A synapse can undergo LTP when the postsynaptic cell receives a strong stimulus, such as a brief high-frequency tetanus.
A synapse can undergo LTD when the postsynapse receives a prolonged low-intensity stimulus.

Input Specificity of LTD

Similar to LTP, LTD is also input-specific, meaning only the stimulated synapses are weakened.

Calcium's Role in LTP vs. LTD

The amount of $Ca^{2+}$ that flows in through NMDA receptors is the key determinant of whether LTP or LTD occurs.

Postsynaptic Calcium as a Trigger

Small increases in intracellular $Ca^{2+}$ activate protein phosphatases, leading to LTD.
Large increases in intracellular $Ca^{2+}$ activate protein kinases, leading to LTP.

LTD Mechanisms

Inward leak of $Ca^{2+}$ through NMDARs due to partial $Mg^{2+}$ block.
Results in small intracellular $Ca^{2+}$ increases.
Modest depolarization of the postsynaptic membrane.
Activation of protein phosphatases by low $Ca^{2+}$ .
Depressed activity of AMPARs/internalization.
Leads to dephosphorylation of AMPARs.
Less membrane depolarization and a lower response.

LTP Mechanisms

High-frequency stimulus.
$Mg^{2+}$ block of NMDARs is removed, allowing $Ca^{2+}$ to flow into the postsynapse.
Results in larger intracellular $Ca^{2+}$ increases.
Activation of protein kinases by high $Ca^{2+}$ .
Phosphorylation of AMPARs.
Increased membrane depolarization and a higher response.

Learning and Memory

Learning: The acquisition of new information.
Memory: The retention of information.

Learning: Habituation (Desensitization)

Habituation is a non-associative form of learning.
It is the decrease in the strength of a behavioral response to a repeated application of a mild stimulus.
The circuit or organism learns to ignore stimuli that are not novel, freeing resources to respond to novel or important stimuli.
Example: Habituation of the gill withdrawal behavior in response to repeated tactile stimulation of the siphon of the marine snail Aplysia californica.

Learning: Sensitization

Increase in behavioral response to a strong/noxious stimulus.
Sensitization can reverse habituation.
The gill withdrawal reflex of Aplysia can be both habituated and sensitized.

Types of Memory

Declarative/Explicit Memory:
- Facts and events (e.g., capitals of countries, events at a party, composition of breakfast).
- Conscious recollection of explicit memories.
Nondeclarative/Implicit Memory:
- Skills and habits (e.g., riding a bike, tying shoelaces, playing an instrument).

Long-Term, Short-Term, and Working Memory

Long-Term Memories: Lasting, stored for days, months, or years (e.g., remembering someone's birthday).
Short-Term Memories: Not lasting, only seconds or hours, and susceptible to disruption.
Working Memory: Retention of information through repetition for short periods, limited capacity (e.g., remembering a phone number).

Medial Temporal Lobe

Important in the formation of declarative memories.
Receives highly processed information from all sensory systems.

Nondeclarative Memory: Classical Conditioning

The temporal pairing of the conditioned stimulus (CS) and unconditioned stimulus (US) is crucial.

Memory Deficits: Amnesia

Deficits in memory formation or the ability to recall formed memories.
Risk factors include chronic alcoholism, concussion, brain tumors, and stroke.
Types of amnesia:
- Retrograde amnesia: Loss of memories for events before the onset of the amnesia.
- Anterograde amnesia: Inability to form new memories after brain trauma.
- Dissociative amnesia: Not caused by physical damage but associated with traumatic events (suppressed memories).

Case of H.M. (Henry Gustav Molaison)

Underwent a bilateral mediotemporal lobectomy at age 27 to stop seizures.
Seizures stopped, but he experienced minor retrograde amnesia and severe anterograde amnesia.
Long-term memory (for older memories) and working memory were present.
Inability to form new declarative memories and spatial memory impairments.

Lessons from the Case of H.M.

Memories are not stored in a single brain area but are stored in various cortical areas depending on the input pathways (e.g., auditory vs. visual).
Structures in the medial temporal lobe are particularly important for long-term memory consolidation.
Structures in the medial temporal lobe are important for declarative memory formation.

Medial Temporal Lobe Structures Involved in Memory

Hippocampus
Entorhinal cortex
Perirhinal cortex
Parahippocampal cortex

Delayed Non-Match to Sample Task

Monkeys with bilateral medial temporal lesions show an increase in errors on this task.
Performance is more accurate with short delays and progressively worsens with longer delays (a few minutes).