Synaptic Plasticity

Synaptic Plasticity

Overview

• Synaptic plasticity refers to the experience-dependent changes in the structure and function of the nervous system, forming the cellular basis for learning and memory.

  • Key Changes: These adaptive changes can occur at various levels within the neuron and synapse:

  • Number of receptors: Alterations in the density or expression of neurotransmitter receptors on the postsynaptic membrane (e.g., AMPA or NMDA receptors).

  • Number of synapses: Formation of new synaptic connections (synaptogenesis) or elimination of existing ones (synaptic pruning).

  • Amount of neurotransmitter released: Changes in the presynaptic terminal's ability to synthesize, store, and release neurotransmitters.

  • Number of neurons: While less common in adult plasticity, neurogenesis (creation of new neurons) can contribute in specific brain regions, like the hippocampus.

  • Effects: These modifications can lead to either a strengthening or weakening of synaptic connections, altering the efficacy of communication between neurons.

  • Temporal Nature: Synaptic plasticity can manifest over different timescales, allowing for rapid adjustments or long-lasting structural changes:

  • Short-term plasticity (milliseconds to minutes): Transient changes in synaptic strength.

  • Long-term plasticity (minutes to potentially permanent): Durable changes that can underlie long-term memory formation.

Learning Outcomes

• Categories of Synaptic Plasticity: Develop the ability to identify, describe, or provide concrete examples of the major forms of synaptic plasticity:

  • Synaptic facilitation: A short-term increase in synaptic strength.

  • Synaptic depression: A short-term decrease in synaptic strength.

  • Habituation: A decrease in behavioral response to a repeated, innocuous stimulus.

  • Sensitization: An increase in behavioral response to a noxious or novel stimulus.

  • Long-term potentiation (LTP): A persistent strengthening of synapses based on recent activity.

  • Long-term depression (LTD): A persistent weakening of synapses based on recent activity.

• Mechanisms:

  • Explain the common underlying presynaptic mechanisms responsible for synaptic facilitation and synaptic depression, focusing on calcium dynamics and vesicle availability.

• Aplysia Study: Discuss in detail the phenomena of habituation and sensitization in Aplysia californica, a crucial model organism, and elucidate the specific molecular mechanisms that mediate these processes at the synaptic level.

• Hippocampus Study: Explain the experimental paradigms used to study, and the fundamental molecular mechanisms underlying, early LTP, late LTP, and LTD in the mammalian hippocampus, as well as LTD in the cerebellum.

• Alteration Consequences: Predict the outcomes or consequences of experimentally altering key molecular components involved in habituation/sensitization in Aplysia, LTP/LTD in the hippocampus, and LTD in the cerebellum, on synaptic function and behavioral output.

• Experimental Design: Propose and design a physiological or molecular experiment to investigate specific alterations in synaptic plasticity, and predict the expected results based on current understanding.

• Comparison: Compare and contrast any two forms of plasticity based on their mechanisms, duration, and functional implications.

• NMDA Receptors: Describe in detail how activity-dependent changes in NMDA receptor subunit composition and trafficking can influence the maintenance of synaptic homeostasis and metaplasticity.

Types of Synaptic Plasticity

• Short-term: These forms of plasticity are transient, typically lasting from milliseconds to a few minutes, reflecting rapid adjustments in synaptic efficacy.

  • Examples:

  • Synaptic facilitation: A temporary increase in neurotransmitter release.

  • Synaptic depression: A temporary decrease in neurotransmitter release.

• Long-term: These forms of plasticity are more enduring, lasting from minutes to hours, days, weeks, or even potentially permanent changes, forming the basis of long-term memory.

  • Examples:

  • Habituation/Sensitization: Behavioral learning processes mediated by long-term changes at specific synapses.

  • Long-term potentiation (LTP): A robust and persistent increase in synaptic strength.

  • Long-term depression (LTD): A robust and persistent decrease in synaptic strength.

Synaptic Facilitation

• Synaptic facilitation is characterized by a significantly larger second postsynaptic potential (PSP) when two presynaptic action potentials arrive in close succession.

• Duration: This enhancement is very brief, lasting only milliseconds, as residual calcium is quickly buffered or pumped out of the presynaptic terminal.

  • Mechanism: The key mechanism involves the residual accumulation of calcium ($Ca^{2+}$) ions within the presynaptic terminal. When the first action potential arrives, $Ca^{2+}$ enters the terminal and triggers neurotransmitter release. Before this $Ca^{2+}$ can be fully cleared, a second action potential arrives, leading to an additional influx of $Ca^{2+}$. This residual $Ca^{2+}$ from the first AP sums with the $Ca^{2+}$ from the second AP, resulting in a higher transient presynaptic $Ca^{2+}$ concentration. This elevated $Ca^{2+}$ enhances the probability of vesicle fusion and neurotransmitter release, leading to a larger postsynaptic response.

Synaptic Depression

• Synaptic depression occurs when high-frequency or sustained presynaptic activity leads to a progressive decline in the amplitude of neurotransmitter release and, consequently, a smaller postsynaptic potential with successive stimuli.

  • Mechanism: The primary mechanism driving synaptic depression is the depletion of the readily releasable pool of synaptic vesicles in the presynaptic terminal. With continuous stimulation, neurotransmitter release outpaces the rate at which vesicles can be refilled and transported to the active zone. This progressive exhaustion of the reserve vesicle pool limits the amount of neurotransmitter available for release, leading to a diminished postsynaptic response over time.

Habituation and Sensitization in Aplysia

• Background: The marine slug Aplysia californica is an extensively studied model organism for investigating the cellular and molecular mechanisms of learning and memory due to its relatively simple nervous system, large and identifiable neurons, and robust behavioral reflexes.

• Gill Withdrawal Reflex: A key behavior studied in Aplysia is its defensive gill withdrawal reflex. Touching or squirting a gentle jet of water on the siphon (a respiratory appendage) normally elicits a stereotypical reflexive withdrawal of the gill.

  • Experimental Illustration: The magnitude and duration of this gill withdrawal decrease significantly and predictably over time with repeated, non-threatening stimuli to the siphon, demonstrating habituation.

• Habituation: This phenomenon is defined as a decreased magnitude of the gill withdrawal response across successive trials (e.g., comparing Trial 1 to Trial 6 and then to Trial 13), indicating that the animal has learned to ignore an innocuous stimulus.

  • Molecular Basis: Habituation at the synaptic level is primarily due to a presynaptic mechanism. With repeated stimulation, there is a progressive decrease in the amount of glutamate released from the siphon sensory neuron onto its postsynaptic motor neuron. This reduced glutamate release leads to a diminished excitatory postsynaptic potential (EPSP) in the motor neuron, thereby producing a reduced contraction of the gill muscle responsible for withdrawal.

Sensitization of Withdrawal Reflex

• In contrast to habituation, if a strong, noxious stimulus (a mild electric shock) is delivered to another part of the animal, such as the head or tail, it greatly amplifies the gill withdrawal response to subsequent siphon stimulation, and this enhanced response can last for approximately one hour or longer.

• Pathway of Sensitization: The sensitization pathway in Aplysia involves several key components:

  • It begins with the activation of a facilitating interneuron, such as L29, by the noxious stimulus. These interneurons are serotonergic (release serotonin, 5-HT).

  • Axo-axonal synapses: The facilitating interneurons form axo-axonal synapses directly onto the presynaptic terminals of the siphon sensory neurons.

  • Motor neuron activation: The serotonin released by L29 modules the sensory neuron, leading to enhanced neurotransmitter release onto the gill motor neuron, which then affects the gill muscle.

Early Sensitization Mechanism

• Serotonin Role: When serotonin (5-HT) is released from the facilitating interneurons, it binds to G-protein coupled receptors on the presynaptic terminal of the siphon sensory neuron. This binding initiates a signaling cascade that ultimately inhibits the opening of specific potassium ($K^{+})$) channels (e.g., S-type $K^{+})$ channels) during action potentials.

• Activation of PKA: Serotonin receptor activation leads to the activation of adenylyl cyclase, increasing the intracellular concentration of cyclic AMP (cAMP). cAMP then activates protein kinase A (PKA). PKA phosphorylates the $K^{+}$ channels, reducing their conductance and prolonging the action potential duration.

• Consequences of K+ Channel Alteration: This inhibition of $K^{+}$ channel opening prolongs the repolarization phase of the action potential. This greater and sustained depolarization of the presynaptic terminal leads to:

  • More calcium ($Ca^{2+}$) channels opening: Voltage-gated $Ca^{2+}$ channels remain open for a longer duration, allowing more $Ca^{2+}$ to influx into the terminal.

  • Increased neurotransmitter release: The elevated presynaptic $Ca^{2+}$ concentration significantly enhances the probability of synaptic vesicle fusion and thus, glutamate release.

  • More vesicles docking at the membrane: The prolonged $Ca^{2+}$ signal also facilitates the mobilization and docking of synaptic vesicles at the active zone, priming them for release.

Effects of Shock on Duration of Sensitization

• The duration and intensity of the sensitizing effect are directly correlated with the strength and number of noxious stimuli (shocks) delivered. Repeated or stronger shocks can lead to more persistent and profound sensitization of the gill withdrawal reflex.

• Repeated shocks significantly enhance and prolong heightened withdrawal responses across longer time intervals, indicating a translation from short-term to long-term sensitization.

Long-Term Potentiation and Long-Term Depression

• LTP and LTD Mechanism: Both LTP and LTD are forms of activity-dependent synaptic plasticity, widely believed to be the cellular underpinnings of learning and memory. They occur due to the precise spatiotemporal activity of presynaptic and postsynaptic neurons, adhering to Hebbian principles.

  • Synapse Strengthening (LTP): The principle often stated as "neurons that fire together, wire together." When a presynaptic neuron repeatedly or strongly excites a postsynaptic neuron, causing it to fire action potentials, the connection between them is strengthened.

  • Synapse Weakening (LTD): Conversely, if neurons fire out of sync, or with low-frequency, the synaptic linking between them can decrease, following the principle "neurons that fire out of sync, lose their link."

• Hippocampus Focus: LTP is one of the most extensively studied forms of synaptic plasticity, particularly in the hippocampus, a brain region critically involved in learning and memory formation. LTP in the hippocampus is typically studied by applying high-frequency stimulation (tetanus) to afferent pathways, which effectively induces a persistent enhancement of synaptic transmission.

Characteristics of LTP

• LTP can last from days to weeks, months, or even a lifetime, representing a durable change in synaptic efficacy. This long-lasting potentiation can occur without needing further tetanus stimulation, provided that both pre- and postsynaptic neurons are capable of being activated together.

Potentiation Specificity

• LTP exhibits input specificity: the potentiation is specific to only those synapses that were active during the induction protocol, leaving inactive or weakly active pathways on the same postsynaptic neuron unaffected. This ensures that learning is targeted and precise.

Glutamate Receptor Overview

• Types: The primary excitatory neurotransmitter in the brain, glutamate, acts on several receptor types, crucial for LTP and LTD:

  • AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid): These are ligand-gated ion channels that primarily allow the rapid influx of sodium ($Na^{+})$) and efflux of potassium ($K^{+}$) ions when glutamate binds. They mediate fast excitatory synaptic transmission and do not require postsynaptic depolarization for opening.

  • NMDA receptors (N-methyl-D-aspartate): These are unique ligand-gated ion channels that require two conditions for full activation and ion flow:

    1. Glutamate binding: Glutamate must bind to the receptor.

    2. Postsynaptic depolarization: The postsynaptic membrane must be sufficiently depolarized to relieve a voltage-dependent magnesium ($Mg^{2+}$) block within the channel pore. Once activated, they facilitate the flow of $Na^{+}$, $K^{+}$, and crucially, $Ca^{2+}$ ions. $Ca^{2+}$ influx through NMDA receptors is a critical trigger for many forms of long-term plasticity.

Early LTP Mechanism

• Early LTP (E-LTP) typically lasts for a few hours and does not require new protein synthesis.

• Upon tetanus-induced (high-frequency) presynaptic depolarization:

  • NMDA receptor channels open: The strong presynaptic activity releases abundant glutamate, and the strong postsynaptic depolarization (due to AMPA receptor activation) simultaneously removes the $Mg^{2+}$ block from NMDA receptors. This allows them to open.

  • $Ca^{2+}$ influx: The opening of NMDA channels results in a significant influx of $Ca^{2+}$ into the postsynaptic neuron.

  • Activation of protein kinases: This transient rise in intracellular $Ca^{2+}$ acts as a second messenger, triggering the activation of various protein kinases, including Protein Kinase C (PKC) and Calcium/Calmodulin-dependent Kinase II (CaMKII).

  • AMPA receptor phosphorylation: These activated kinases rapidly phosphorylate existing AMPA receptors, which enhances their ion conductance and makes them more responsive to glutamate.

  • Increase AMPA receptor numbers (receptor trafficking): The kinases also promote the insertion of new AMPA receptors from intracellular stores into the postsynaptic membrane (a process known as receptor trafficking). This increases the total number of functional AMPA receptors at the synapse, making the postsynaptic neuron more sensitive to subsequent glutamate release from the presynaptic neuron.

Silent Synapses and AMPA Inclusion

• Silent synapses are a unique type of synapse characterized by the presence of functional NMDA receptors but a complete lack of functional AMPA receptors in their postsynaptic membrane. They are typically 'silent' at resting membrane potentials because the $Mg^{2+}$ block prevents current flow through NMDA receptors. Through robust LTP processes, these silent synapses can mature into functional synapses by the insertion of AMPA receptors into their membrane, thereby making them responsive to normal synaptic activity.

Late LTP

• Late LTP (L-LTP) represents a more enduring form of potentiation, lasting for many hours to days or longer, and unlike E-LTP, it is critically dependent on de novo protein synthesis.

• Late-phase potentiation is initiated by a more prolonged or stronger $Ca^{2+}$ entry, which often results from extended high-frequency stimulation. This sustained $Ca^{2+}$ signal activates additional signaling pathways that lead to changes in gene expression and protein synthesis.

  • Activation of transcription factors: Key transcription factors, such as CREB (cAMP Response Element-Binding protein), become activated. Activated CREB binds to specific DNA sequences, promoting the transcription of immediate early genes.

  • Production of new synapses: The proteins synthesized as a result of this gene expression include structural proteins, adhesion molecules, and components necessary for the formation of new synaptic connections (synaptogenesis) or the enlargement of existing ones. This results in the growth of new dendritic spines and the creation of new synapses over time between neuronal pairs, leading to more robust and stable connections.

  • Protein synthesis is crucial: This de novo protein synthesis is absolutely essential for maintaining the long-term changes associated with L-LTP. Inhibitors of protein synthesis block L-LTP but not E-LTP.

Longevity of LTP

• The profound and long-lasting nature of LTP is demonstrated by recorded excitatory postsynaptic potential (EPSP) amplitudes from action potentials that exhibit robustness and increased size weeks and even months post-stimulation. This longevity reflects not just functional changes but often structural modifications, such as increased spine head size and new spine formation, which physically strengthen the synaptic connection.

Long-Term Depression (LTD)

• General Mechanism: Long-term depression (LTD) is a sustained weakening of synaptic strength, typically induced by prolonged low-frequency stimulation of the presynaptic neuron, particularly under weak postsynaptic depolarization conditions. In contrast to LTP, LTD often involves metabolizing $Ca^{2+}$ signaling to activate protein phosphatases rather than kinases. These phosphatases remove phosphate groups from AMPA receptors, affecting their presence and function at the postsynaptic membrane.

LTD Mechanism in Hippocampus

• In the hippocampus, LTD is primarily induced through weak and prolonged NMDA receptor activation during low-frequency stimulation. This leads to a smaller and more gradual $Ca^{2+}$ influx compared to LTP.

• This modest but sustained rise in intracellular $Ca^{2+}$ preferentially activates protein phosphatases (such as calcineurin and protein phosphatase 1, PP1). These phosphatases dephosphorylate AMPA receptors and trigger their internalization from the postsynaptic membrane (endocytosis), reducing the number of functional AMPA receptors and thereby weakening the synaptic response.

LTD in Cerebellum Context

• LTD in the cerebellum is crucial for motor learning and coordination. Cell activity related to movement control and motor skill acquisition (e.g., learning a new motor task or adapting to changes in dynamics) is observed in the cerebellum. Here, LTD results in adaptability to improve future performance based on error signals and feedback processing, fine-tuning motor commands.

Cellular Basis of LTD in Cerebellum

• Cerebellar LTD occurs at the synapses between parallel fibers (inputs from granule cells) and Purkinje cells (the sole output neurons of the cerebellar cortex). It is a highly specific form of synaptic weakening that requires the simultaneous activation of specific pathways:

  • Parallel fibers release glutamate, activating glutamate receptors (AMPA and metabotropic glutamate receptors, mGluRs) on the Purkinje cell dendritic spines.

  • Climbing fibers (carrying error signals from the inferior olive) cause a large, complex depolarization in the Purkinje cell, leading to significant $Ca^{2+}$ influx.

  • The precisely timed co-activation of parallel fibers and climbing fibers leads to a unique signaling cascade. Glutamate binding to mGluRs activates Protein Kinase C (PKC) via a G-protein cascade and diacylglycerol (DAG) production. The $Ca^{2+}$ influx from climbing fiber activity further activates PKC.

  • The combined activation of PKC causes the phosphorylation of specific proteins that regulate AMPA receptor trafficking. This ultimately leads to the internalization and removal of AMPA receptors from the postsynaptic membrane of the Purkinje cell, thus regulating (weakening) synaptic transmission at that specific parallel fiber-Purkinje cell synapse and allowing for motor learning.

Synaptic Homeostasis

• Synaptic homeostasis refers to mechanisms that maintain synaptic strength and network activity within a physiological range, preventing runaway excitation or depression that could impair brain function. Moderate NMDA receptor activity plays a crucial role in maintaining synapse strength by balancing processes that lead to potentiation and depression.

  • Metaplasticity: This concept describes how the history of synaptic activity can influence the threshold or susceptibility for inducing subsequent plasticity. Shifts in the subunit composition or activity levels of NMDA receptors (e.g., changes in the ratio of GluN2A to GluN2B subunits, which alters $Ca^{2+}$ dynamics) can significantly influence the tendency of a synapse to undergo LTP or LTD. For example, synapses with a higher proportion of GluN2B subunits might have a lower threshold for LTP induction.