Synaptic Plasticity PDF

Neurophysiology – Buffo (Lesson 7b) BN8 Synaptic Plasticity Synaptic plasticity refers to the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity. This phenomenon is considered a cellular mechanism underlying learning and memory. Historical...

Neurophysiology – Buffo (Lesson 7b) BN8 Synaptic Plasticity Synaptic plasticity refers to the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity. This phenomenon is considered a cellular mechanism underlying learning and memory. Historical Foundations 1. Santiago Ramón y Cajal (1894): Santiago Ramón y Cajal, a pioneering neuroscientist and often regarded as the father of modern neurobiology (together with Golgi), proposed an early theory about how memories might be formed at the cellular level. He suggested that memories are created through the strengthening of connections (synapses) between existing neurons. Cajal hypothesized that repeated and persistent activity between two connected neurons would enhance the efficiency of their communication. This idea aligns with what we now understand as synaptic plasticity: the strengthening of synaptic connections based on activity. Synaptic Strengthening: When two neurons frequently activate together, the synapse (connection) between them becomes stronger, facilitating more efficient communication. This enhanced synaptic efficacy is crucial for the storage of memories. 2. Donald O. Hebb (1949): Donald O. Hebb, a Canadian psychologist, further developed the concept of synaptic plasticity with his famous postulate, often summarized by the phrase "cells that fire together, wire together." Hebb proposed that when a presynaptic neuron (neuron A) repeatedly activates a postsynaptic neuron (neuron B), some persistent change occurs that increases the likelihood of neuron B being activated by neuron A in the future. This could involve growth processes or metabolic changes in the neurons, leading to increased synaptic strength. Hebbian Plasticity: The principle that the simultaneous activation of cells leads to pronounced increases in synaptic strength between those cells. This process underpins learning and memory at the cellular level. Cellular Mechanisms of Synaptic Plasticity Synaptic plasticity can be broadly categorized into short-term and long-term plasticity, depending on the duration of the changes in synaptic strength. Short-Term Synaptic Plasticity 1) Short-term facilitation Short-term facilitation is a temporary increase in synaptic strength that occurs on a timescale of tens of milliseconds. This form of plasticity enhances the postsynaptic response following closely spaced presynaptic action potentials. When two presynaptic action potentials occur in rapid succession (separated by a few milliseconds, typically less than 10-20 milliseconds), the postsynaptic response to the second action potential is significantly enhanced compared to the first. This enhancement is observed as a larger postsynaptic depolarization in response to the second action potential. Mechanism: 1. When an action potential arrives at the presynaptic terminal, it triggers an influx of calcium ions (Ca²⁺) into the presynaptic neuron. 2. If a second action potential follows closely after the first, before the calcium levels have returned to baseline, the residual calcium from the first action potential combines with the calcium influx from the second. 3. This accumulation of calcium leads to an increased concentration of Ca²⁺ in the presynaptic terminal. 4. Higher presynaptic Ca2+ concentration enhances the release of neurotransmitters into the synaptic cleft. 5. Consequently, the postsynaptic response to the second action potential is more robust compared to the first, resulting in a greater depolarization of the postsynaptic neuron (enhanced second response). Features: Critical Timing: The extent of facilitation critically depends on the interval between the presynaptic stimuli. The shorter the interval (within the range of less than 10-20 milliseconds), the greater the facilitation (prevention of calcium clearance). Transient Nature: This form of plasticity is short-lived, with effects lasting tens of milliseconds. Short-term facilitation allows synapses to modulate their strength rapidly in response to the temporal pattern of neural activity. This transient boost in synaptic efficacy can enhance signal transmission during high-frequency bursts of activity, playing a crucial role in processes such as attention, sensory perception, and the initial stages of memory formation. 2) Short-Term Synaptic Depression (STD) Short-term depression (STD) is another form of synaptic plasticity that occurs over a timescale of tens of milliseconds. It is characterized by a decrease in the efficacy of synaptic transmission following repetitive presynaptic stimulation → During repetitive presynaptic stimulation, the speed of the postsynaptic response progressively decreases, indicating a reduction in synaptic efficacy. This decrease is observed over the same short temporal scale as short-term facilitation. NB: The y-axis of the graph represents the speed of the postsynaptic response, indicating how rapidly the postsynaptic membrane depolarizes in response to presynaptic input. STD is influenced by extracellular calcium (Ca²⁺) levels. When normal levels of extracellular calcium are present, repeated stimulation of a postsynaptic neuron leads to a decline in the speed and magnitude of the response. Reducing extracellular calcium concentration can alter this depressive response. Lower calcium levels can sometimes result in a facilitation-like response, indicating the critical role of calcium influx in this process. Mechanism → Vesicle Depletion Hypothesis (Vesicle Availability): The primary mechanism underlying STD is the depletion of readily releasable synaptic vesicles. With repeated, high-frequency presynaptic stimulation, the pool of available neurotransmitter-filled vesicles gets depleted faster than it can be replenished. In fact, after intense stimulation, there is a period during which the efficacy of the response remains low until the vesicle pool is replenished from a reserve pool. 3) Synaptic Augmentation & Potentiation Synaptic augmentation and potentiation are two forms of synaptic plasticity that enhance neurotransmitter release from presynaptic terminals. Both synaptic augmentation and potentiation are crucial for extending the impact of synaptic activity beyond immediate responses. They rely on enhancing the mechanisms that govern synaptic vesicle fusion and neurotransmitter release, with augmentation primarily involving SNARE proteins and potentiation involving both SNARE proteins and synapsin. They differ in their timescales and mechanisms but both ultimately increase the efficacy of synaptic transmission in response to repeated synaptic activity. Synaptic Augmentation Timescale: few seconds. Mechanism: Increased Neurotransmitter Release: Repeated synaptic activity leads to an increased amount of neurotransmitter released from the presynaptic terminals. Augmentation enhances the ability of incoming calcium (Ca²⁺) to trigger the fusion of synaptic vesicles with the plasma membrane, facilitating neurotransmitter release. SNARE Proteins: This process is thought to be SNARE protein-dependent. SNARE proteins are crucial for the fusion of synaptic vesicles with the presynaptic membrane. Experimental Context → Low Calcium Conditions: Studies at the giant squid synapse under low extracellular calcium concentrations have shown that augmentation can still potentiate the postsynaptic response, suggesting an enhanced activity of SNARE proteins. Synaptic Potentiation Timescale: longer timescale, lasting tens of seconds to minutes. Mechanism: Prolonged Enhancement: The increased synaptic response can outlast the period of stimulation, especially following high-frequency, intense stimulation known as tetanic stimulation. NB: Tetanic Stimulation = very intensive stimulation that induces the generation of action potential at the maximum speed in neurons. Post-Tetanic Potentiation (PTP): Potentiation that lasts for minutes after tetanic stimulation is referred to as post-tetanic potentiation. Calcium and Synapsin Dependency: Potentiation enhances the ability of calcium to trigger vesicle fusion, similar to augmentation, but is also dependent on synapsin proteins. Synapsin is involved in mobilizing synaptic vesicles from a reserve pool to the readily releasable pool, thereby sustaining neurotransmitter release. Experimental Context → Tetanic Stimulation: In spinal motor neurons, tetanic stimulation leads to maximum action potential generation, resulting in PTP. This phenomenon is synapsin-dependent, as synapsin plays a critical role in maintaining vesicle availability for release. Dynamic Regulation of Synaptic Transmission During repetitive synaptic activity, various forms of short-term plasticity interact to modulate synaptic transmission. Interactions at a neuromuscular synapse in response to repetitive stimulation: Presynaptic Stimulation Pattern (Top Panel): shows the pattern of repetitive presynaptic stimulation applied to the synapse. The stimulation consists of high-frequency action potentials, followed by a single action potential applied 30 seconds later. Postsynaptic Membrane Potential (Middle Panel): depicts the changes in the postsynaptic membrane potential over time in response to the presynaptic stimulation. The membrane potential initially rises sharply, peaks, then gradually declines, and finally shows a secondary increase when stimulated by a single action potential 30 seconds later. Relative Amount of Transmitter Release (Bottom Panel): represents the relative amount of neurotransmitter released over time, correlating with the changes in postsynaptic membrane potential. The graph highlights the interaction of different forms of synaptic plasticity: facilitation, augmentation, depression, and potentiation. Long-Term Synaptic Plasticity The transition from short-term to long-term synaptic plasticity has been elucidated through various studies, notably those involving the mollusk Aplysia. This organism was intensively studied by Eric Kandel and his team, leading to insights that earned Kandel the Nobel Prize. Aplysia serves as an advantageous model due to the well-mapped neural circuits controlling specific behaviors, which can be easily manipulated ex vivo. This model provides a clear link between neural circuit function and behavior, facilitating studies that are more challenging in vertebrates. The molecular mechanisms supporting long-term synaptic plasticity involve changes in gene expression and protein synthesis. Experimental Observations: Simple Touch: Repeatedly touching the siphon alone leads to habituation, reducing the gill contraction response. o Habituation: When the siphon of Aplysia is repeatedly touched, the gill contraction response diminishes over time, indicating habituation. The animal learns to consider the repeated touch as a non-threatening stimulus, leading to a reduced response. Paired Stimulation: Pairing the siphon touch with a tail shock leads to sensitization, resulting in a robust gill contraction even after habituation. This demonstrates associative learning, where the initially neutral touch becomes conditioned to elicit a response. o Sensitization: If the siphon touch is paired with an aversive stimulus, such as a shock to the tail, the gill contraction response is restored and even enhanced. This response can last for varying durations, from short-term to long-term, depending on the pairing frequency and intensity of the stimuli. Associative Learning in Aplysia can be understood through classical (Pavlovian) conditioning that leads to the formation of memories: Unconditioned Stimulus (US): The tail shock, which naturally induces a gill contraction. Conditioned Stimulus (CS): The siphon touch, which initially does not induce a strong response. Conditioned Response (CR): After pairing the CS (siphon touch) with the US (tail shock), the siphon touch alone elicits a gill contraction. This associative learning showcases how synaptic plasticity underlies behavioral changes, transitioning from short-term to long-term memory based on the frequency and intensity of paired stimuli. 1. Short-Term Memory: Involves temporary changes in synaptic strength due to repeated stimulation. For example, a single tail shock paired with a siphon touch leads to a gill contraction response lasting about one hour. 2. Long-Term Memory: Requires more extensive training, with multiple pairings of the siphon touch and tail shock.  Leads to long-lasting changes in synaptic strength and behavior, transitioning from short-term to long-term memory. Habituation Habituation is a form of non-associative learning where repeated exposure to a benign stimulus leads to a decrease in response. Mechanism: Explained by a reduction in neurotransmitter release from the sensory neurons to the motor neurons due to decreased vesicle availability. In the context of the gill withdrawal reflex: Habituation is characterized by a reduction in the excitatory postsynaptic potential (EPSP) in the motor neurons. This is due to a decreased release of glutamate from the sensory neurons connected to the siphon. The reduction in glutamate release is caused by a decrease in the number of synaptic vesicles that release the neurotransmitter onto the motor neurons. This results in a weaker depolarization and thus a reduced response in the motor neuron. Sensitization Sensitization is a form of associative learning where a benign stimulus paired with a noxious stimulus leads to an increased response. Mechanism: Involves the activation of modulatory interneurons, which enhance neurotransmitter release from the siphon sensory neurons, thus potentiating the motor neuron response. 1. Tail Shock: When a noxious stimulus (e.g., an electric shock) is applied to the tail, the sensory neurons from the tail are activated and transmit this information to the modulatory interneurons.  2. Modulatory Interneurons (= Facilitatory Interneurons) release serotonin at the terminals of the siphon sensory neurons. 3. Presynaptic Facilitation: o The serotonin released by the modulatory interneurons binds to metabotropic receptors on the presynaptic terminal of the siphon sensory neurons. o This binding activates G-proteins, which in turn increase cyclic AMP (cAMP) levels. o cAMP activates protein kinase A (PKA): 1- PKA phosphorylates voltage-gated potassium channels, reducing their activity and thereby prolonging the action potential. 2- PKA also enhances the activity of voltage-gated calcium channels, increasing calcium influx. 4. Enhanced Glutamate Release: The combined effects of prolonged action potentials and increased calcium influx result in more glutamate being released from the siphon sensory neurons onto the motor neurons. This leads to an increased EPSP in the motor neurons, resulting in a stronger gill contraction. Duration of Sensitization: Short-Term Sensitization: The presynaptic facilitation and increased neurotransmitter release can last up to about an hour. Long-Term Sensitization: If the tail shock is repeated or sufficiently strong, longer- lasting changes occur that involve gene expression and new protein synthesis. Structural Plasticity: Synaptic plasticity can lead to changes in circuit function and to behavioral plasticity. Plastic changes in synaptic function can be either: 1. Short-term effects that rely on post- translational modification of existing synaptic proteins. 2. Long-term changes that require changes in gene expression, new protein synthesis, and growth of new synapses (as well as enlarging or eliminating existing synapses). o Synaptic Growth: growth of new synaptic terminals and an increase in the number of synaptic vesicles. o Local mRNA Synthesis: Persistent activation of PKA also stimulates local mRNA synthesis in the presynaptic terminal. o Synaptic Pruning: reduction of useless synapses to optimize the circuitry of the most used ones. Long-Term Synaptic Plasticity in Mammalian Cells In mammalian cells, long-term forms of synaptic plasticity, namely Long-Term Potentiation (LTP) and Long-Term Depression (LTD), are fundamental mechanisms underlying memory formation and learning. These processes are particularly well-studied in the hippocampus, a brain region crucial for memory processing. The Hippocampal Circuitry and Synaptic Plasticity The hippocampus has been extensively studied in both rodent models and humans due to its pivotal role in forming new memories. The hippocampal circuit involved in synaptic plasticity is relatively simple and includes several key pathways: 1. Perforant Pathway: Input from Cortices: Sensory and associative information from various cortical areas enters the hippocampus via the perforant pathway. Synapse on Dentate Gyrus: The perforant pathway fibers synapse onto the granule cells in the dentate gyrus. 2. Dentate Gyrus: Granule Cells: Receive inputs from the perforant pathway and project their axons, known as mossy fibers, to the CA3 region of the hippocampus. 3. CA3 Region: Pyramidal Cells: Mossy fibers from the dentate gyrus synapse onto the pyramidal cells in the CA3 region. Schaffer Collaterals: The axons of CA3 pyramidal cells, known as Schaffer collaterals, project to and synapse onto pyramidal cells in the CA1 region. 4. CA1 Pyramidal Cells. Long-Term Potentiation (LTP) LTP involves a long-lasting enhancement in signal transmission between two neurons that results from their synchronous stimulation. When neuron A and neuron B fire together repeatedly, the synapse between them becomes potentiated, meaning its efficacy is increased. The potentiation can last from hours to days, or even longer, depending on the specific circumstances and neural circuits involved. This form of plasticity is critical for learning and memory formation. Mechanism: 1) Induction: High-Frequency Stimulation: LTP is typically induced by high-frequency stimulation of synaptic pathways, leading to sustained depolarization of the postsynaptic neuron. 2) Molecular Mechanisms:  NMDA Receptor Activation: Sustained depolarization removes the Mg²⁺ block from NMDA receptors, allowing calcium (Ca²⁺) influx. Calcium Signaling: The influx of Ca²⁺ activates calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), which phosphorylate various proteins. AMPA Receptor Trafficking: Phosphorylation increases the insertion and activity of AMPA receptors in the postsynaptic membrane, enhancing synaptic strength. 3) Maintenance: Gene Expression and Protein Synthesis: Long-term maintenance of LTP involves changes in gene expression and protein synthesis, leading to structural changes such as the growth of new dendritic spines. Repeated stimulation leads to persistent activation of PKA, which can eventually translocate to the nucleus. PKA in the nucleus activates the transcription factor CREB (cAMP Response Element- Binding Protein), which promotes the expression of genes involved in synaptic growth and stability. These genes encode for proteins that contribute to the formation of new synaptic connections and the strengthening of existing ones. Various protocols for Inducing LTP → To reliably induce LTP in a neural circuit, a protocol known as tetanic stimulation can be used: Tetanic Stimulation: involves delivering a high-frequency burst of stimuli (typically around 100 Hz) to the presynaptic neuron. In the hippocampal region, this often targets the Schaffer collateral fibers which connect CA3 and CA1 pyramidal neurons. When tetanic stimulation is applied: 1- There is an immediate and significant increase in the postsynaptic potential. NB: Early Phase LTP (E-LTP): involves changes that do not require new protein synthesis. It is primarily mediated by the phosphorylation of existing proteins and changes in the number and sensitivity of postsynaptic receptors. 2- Following the initial peak, there is a phase of sustained enhancement where the postsynaptic response remains elevated. This can be maintained for hours, days, or even longer, representing a stable form of synaptic plasticity. NB: Late Phase LTP (L-LTP): requires gene transcription and new protein synthesis. It is associated with more long-lasting structural changes, such as the growth of new synaptic connections.  NB: HFS → Square Pulse of Maximal Action Potential production. NB: HFS and TBS give the same response. NB: In Pairing Protocol both components are active together. Factors Influencing LTP: 1) Frequency of Stimulus Weak High-Frequency Stimulation: High-frequency stimulus at a lower intensity result in transient potentiation (= increase in synaptic strength is temporary and fades over time). Strong High-Frequency Stimulation: High-frequency stimulus applied at a higher intensity, leads to stable LTP. This form of potentiation is long-lasting and represents a more durable increase in synaptic strength. Single Tetanus: A single burst of high-frequency stimulation (tetanus) can induce LTP lasting several minutes to a few hours. Repeated Trains: Multiple repeated trains of stimulation can extend LTP from hours to days. This extended duration reflects the cumulative effect of repetitive stimulation. 2) Strength of the Stimulus LTP induction depends on two key components: the frequency of the stimulation and the strength of the stimulus. Both components can compensate for each other to some extent. a) Frequency Component: How rapidly the stimuli are delivered. b) Strength Component: Intensity or amplitude of the stimuli. The interaction between the frequency and strength of stimulation is crucial. Stronger stimuli can compensate for lower frequencies, and higher frequencies can compensate for weaker stimuli. This means that either increasing the frequency or the strength of the stimulus can effectively induce LTP. Features of LTP: 1. Coincidence Detection (strong activity in pre- and post-synaptic sites): LTP requires simultaneous activity in both presynaptic and postsynaptic neurons. For LTP to be induced, postsynaptic depolarization must occur within approximately 100 milliseconds of neurotransmitter release from the Schaffer collaterals. Even subthreshold depolarization (a very mild stimulus) can be sufficient to induce LTP if it occurs within this critical time window.  2. Associativity: LTP is associative, meaning it can bind together inputs from different sources if they occur within a short time window (= binds together neurons that are active together). When a weak input (subthreshold) and a strong input (suprathreshold) arrive simultaneously at the postsynaptic neuron, both inputs can be potentiated, leading to LTP. This associative property is crucial for linking different aspects of a single stimulus, such as the color and smell of a rose, into a coherent memory. This form of associative learning, where different sensory inputs are integrated, is the cellular basis for complex learning processes such as Pavlovian conditioning. 3. Specificity: LTP occurs specifically at the synapses that receive sufficient stimulation. It is not a global property of the entire neuron but is localized to particular synaptic sites. The specificity allows for targeted strengthening of synaptic connections, which can persist for extended periods, ranging from minutes to years. LTP and Hebb's Postulate Long-term potentiation (LTP) embodies the principles of Hebb's postulate, which states that "cells that fire together, wire together." This process is characterized by coincidence detection, associativity, and specificity, making it a fundamental mechanism in learning and memory formation. Properties Expected of a Physiological Basis for Memory: o Rapid Induction: LTP can be induced within seconds, allowing for quick adjustments in synaptic strength in response to new information. o Graded: The strength of LTP can be modulated by the frequency and intensity of stimulation, allowing for fine-tuning of synaptic responses. o Associative: LTP can integrate multiple inputs occurring simultaneously, supporting complex associative learning. o Persistent: Once induced, LTP can last for months or even longer, providing a durable basis for long-term memory. o Synapse-Specific: LTP occurs only at synapses that are appropriately stimulated, maintaining the specificity of neural circuits. o Induced by Physiological Stimuli: Physiological patterns of stimulation, such as theta-burst stimulation, which mimic natural hippocampal rhythms, can induce LTP. Molecular Mechanism: Early-Phase LTP (E-LTP): This phase lasts 1 to 2 hours after LTP induction and relies heavily on post-translational modifications (e.g. phosphorylation of proteins already presents at the synapse). Molecular Mechanisms: The induction and maintenance of LTP primarily involves the interaction between NMDA receptors and AMPA receptors at the synaptic junction.  1. Release of Glutamate: The process begins with the release of the neurotransmitter glutamate from the presynaptic neuron into the synaptic cleft. 2. Activation of AMPA Receptors: Glutamate binds to AMPA receptors on the postsynaptic membrane, causing these receptors to open and allow sodium ions (Na⁺) to enter the postsynaptic neuron. This influx of sodium ions depolarizes the postsynaptic membrane. 3. Depolarization and NMDA Receptor Activation: If the depolarization is sufficient, it relieves the magnesium (Mg²⁺) block from NMDA receptors. 4. Glutamate can now also bind to and activate NMDA receptors, allowing calcium ions (Ca²⁺) to flow into the postsynaptic neuron. 5. The influx of Ca²⁺ acts as a critical second messenger that initiates various intracellular signaling cascades necessary for LTP. NB: Calcium influx is crucial for both the induction and the early maintenance of LTP. 6. Post-Translational Modifications: Calcium activates several kinases, including protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). 7. These kinases phosphorylate various substrates, leading to post-translational modifications that increase the efficiency and number of AMPA receptors on the postsynaptic membrane. o Phosphorylation of AMPA receptors enhances their conductance. o Additionally, more AMPA receptors are trafficked from intracellular stores (recycling endosomes) to the postsynaptic membrane, increasing the postsynaptic neuron's sensitivity to glutamate. Late-Phase LTP (L-LTP): >2 hours after LTP is induced The transition from E-LTP to L-LTP, which occurs approximately 2 hours after LTP induction, requires new protein synthesis. Post-translational modifications alone are insufficient to maintain potentiation in the long term. 1. Local Protein Synthesis: o mRNAs are localized at the dendritic spines, ready for translation upon synaptic activation. o Local protein synthesis allows for rapid and targeted production of proteins necessary for synaptic modifications. 2. Nuclear Transcriptional Regulation: o Activation of protein kinases (e.g., CaMKII, PKA) leads to an increase in the concentration of cAMP via the activation of adenylyl cyclase. o Elevated cAMP levels activate protein kinase A (PKA), which then phosphorylates and activates transcription factors like CREB (cAMP response element-binding protein). o CREB, once activated, promotes the transcription of genes encoding proteins essential for synaptic growth, dendritic spines growth and stability (necessary for LTP).  Structural Changes: The proteins synthesized during L-LTP contribute to structural changes at the synapse, including the growth of new dendritic spines and the formation of new synaptic contacts. This structural plasticity is essential for the maintenance of long-term synaptic potentiation. Silent Synapses Silent synapses are synaptic connections that, during certain developmental stages or conditions, contain NMDA receptors but lack AMPA receptors. Because NMDA receptors alone cannot generate a postsynaptic current in response to neurotransmitter release, these synapses are termed "silent." Silent synapses are characterized by the exclusive presence of NMDA receptors on their postsynaptic sites. NMDA receptors require strong postsynaptic depolarization to remove the magnesium (Mg²⁺) block and allow calcium (Ca²⁺) influx, but they do not independently mediate excitatory postsynaptic currents (EPSCs) unless AMPA receptors are also present. During periods of heightened synaptic activity, nearby active synapses can generate strong postsynaptic calcium influx. If this calcium concentration is sufficiently high, it can diffuse to adjacent silent synapses. The calcium influx activates intracellular signaling pathways in the silent synapse. These pathways initiate the insertion of AMPA receptors into the postsynaptic membrane → The key event in transitioning a silent synapse to an active one is the incorporation of AMPA receptors into the postsynaptic membrane. This insertion increases the synapse's responsiveness to glutamate, allowing it to contribute to synaptic transmission and plasticity. The transformation of silent synapses is closely linked to both structural and functional plasticity: Functional Plasticity: involves changes in synaptic efficacy and strength. For silent synapses, the transition from being functionally inactive to active. Structural Plasticity: refers to changes in the physical characteristics of synapses, such as their size and shape. As silent synapses acquire AMPA receptors, their morphology often changes to accommodate new receptors and enhance synaptic function.  NB: During LTP, the spines of active synapses often undergo structural changes, such as enlargement, which enhances their ability to support increased synaptic activity. Similarly, silent synapses transitioning to an active state may exhibit changes in spine morphology, reflecting their new functional role. Challenge of Protein Turnover in Long-Term Synaptic Plasticity A major challenge in transitioning from short-term to long-term synaptic plasticity, and in forming long-term memories, is the rapid turnover of proteins in the cell. Many proteins are quickly replaced, often within minutes to hours. This rapid turnover means that relying solely on post-translational modifications or the insertion of new proteins into the membrane might not sustain synaptic changes long enough to support long-term memory formation. One effective mechanism to address this challenge is the Autophosphorylation of Kinases. This process can prolong the activity of Kinases (enzymes), making their activation independent of the initial triggering stimulus → Autophosphorylation of Calcium/Calmodulin Kinase (CaMKII): o When CaMKII is activated by calcium influx, it undergoes autophosphorylation. This modification allows the kinase to remain active even after the initial calcium signal has dissipated. o The stabilized active form of CaMKII can then continue to phosphorylate various substrates, including newly synthesized proteins and CREB. This ensures that the changes initiated by CaMKII are sustained over a longer period because can continue to influence cellular processes even as individual protein molecules turn over. The combined actions of autophosphorylation and gene regulation contribute to structural plasticity, which is essential for long-term potentiation (LTP) and memory formation: Formation and Stabilization of New Synaptic Structures: New proteins synthesized as a result of kinase activity and gene regulation support the formation of new dendritic spines and synapses. Permanent Changes and Structural Plasticity: The continuous synthesis of new proteins and the lasting activation of kinases lead to structural changes that underpin long-term synaptic plasticity. These permanent alterations in the synaptic architecture help maintain the enhanced synaptic response necessary for long-term memory. Structural Plasticity and Spine Turnover example in Long-Term Potentiation (LTP) Structural plasticity involves changes in the number and structure of dendritic spines, which are the sites of synaptic contact. LTP is often accompanied by the formation of new spines, enhancing synaptic connectivity. Steps of Structural Plasticity in Dendritic Spines: 1- Formation of New Spines:  Initial spines often appear as simple filopodia. Over time, filopodia can mature into more stable spines, strengthening the synaptic connections. 2- Stabilization and Division of Existing Spines: Stable spines, such as those with a mushroom-like shape, can further enhance synaptic connectivity by dividing into two separate spines, effectively increasing the number of synaptic contacts. Example of Molecular Mechanisms Supporting New Spine Formation: To understand how new spines are formed and stabilized, we can look at specific examples involving striatal medium spiny neurons studied ex vivo: Nucleus-to-Synapse Communication in Synaptic Plasticity Long-term potentiation (LTP) and other forms of synaptic potentiation are highly input-specific, meaning they occur at particular post-synaptic sites in response to specific stimuli. This specificity raises important questions about how the nucleus, which is located far from these synaptic sites, communicates with and regulates these precise locations. LTP and synaptic potentiation are input-specific, meaning they only occur at synapses that receive specific activation. NB: Some synapses can transition from a "silent" state (where they are not actively transmitting signals) to an "active" state, depending on the activation level of nearby synapses. Communication Between Nucleus and Synapses: Given the distance between the nucleus and the postsynaptic sites, a key question arises: How can the nucleus communicate effectively with specific synaptic sites to modulate and potentiate them? Additionally, how can proteins synthesized in the nucleus be selectively targeted to the specific synapses that need potentiation? Synaptic Tagging and Capture (STC) Hypothesis: The STC hypothesis provides a potential explanation for the selective targeting. It proposes that when protein components (and possibly organelles) are synthesized to support LTP, they are "tagged" in a way that allows them to be recognized and utilized by specific postsynaptic sites. This tagging ensures that the newly synthesized proteins are delivered exclusively to the synapses that require them, supporting the sustained potentiation of those synapses. There is some evidence supporting the existence of the STC mechanism, but the details and strength of this evidence are not yet well understood. The process involves not only the synthesis and tagging of proteins but also the transfer of mRNA to the synaptic sites. These mRNAs can be translated locally at the synapse, allowing for a more direct and rapid response to synaptic activity. Long-Term Depression (LTD) LTD is a process that weakens synaptic connections. It occurs when synaptic activity is persistent but at a low frequency, leading to a decrease in synaptic strength. This mechanism is essential for synaptic pruning and the removal of outdated or unnecessary synaptic connections, thereby refining neural circuits. Both LTP and LTD can occur within the same neural circuits. Mechanism: 1) Induction: Low-Frequency Stimulation: LTD is typically induced by low-frequency stimulation of synaptic pathways. 2) Molecular Mechanisms: NMDA Receptor Activation: Like LTP, LTD involves NMDA receptor activation, but the resulting Ca²⁺ signal is weaker and activates different pathways. Protein Phosphatases: The influx of Ca²⁺ activates protein phosphatases, such as calcineurin and protein phosphatase 1 (PP1), which dephosphorylate target proteins. AMPA Receptor Internalization: Dephosphorylation leads to the removal of AMPA receptors from the postsynaptic membrane, weakening synaptic strength. 3) Maintenance: Long-Term Changes: LTD also involves long-term changes in gene expression and protein synthesis, but these changes result in synaptic pruning and reduction of dendritic spines. LTP vs LTD Type of Stimulation: o LTP: Induced by high-frequency stimulation. o LTD: Induced by low-frequency stimulation, such as 1 Hz for 15 minutes. Calcium Dynamics: o LTP: Triggered by a rapid and intense increase in postsynaptic calcium levels. o LTD: Triggered by a slow and moderate increase in postsynaptic calcium levels. Key Molecular Players: o Both LTP and LTD involve AMPA and NMDA receptors. Diversity of LTD: o Unlike LTP, which is relatively uniform across different sites, LTD exhibits greater diversity in its molecular mechanisms and can involve different pathways and molecules depending on the specific neural circuit. Phases of LTD Early Phase LTD Activation of phosphatases such as calcineurin (a calcium-dependent phosphatase).  Calcineurin dephosphorylates various substrates, leading to the internalization of AMPA receptors. This internalization reduces the number of AMPA receptors on the postsynaptic membrane, decreasing synaptic sensitivity and strength. Late Phase LTD Sustained activity of phosphatases and other early-phase mechanisms leads to the activation of transcription factors like CREB. CREB activation promotes the synthesis of new proteins that contribute to the maintenance of LTD. These newly synthesized proteins participate in processes that stabilize the decreased synaptic response. Peculiarities of LTD Site-Specific Mechanisms: LTD can occur at various sites within the CNS, and the underlying molecular mechanisms can differ depending on the specific synapse. Adaptation and Learning: LTD is associated with habituation, an adaptive process where an organism reduces its response to a stimulus that is no longer predictive of significant outcomes. This decrease in response is not passive; it is an active form of learning, allowing the organism to focus on more relevant stimuli. Example: LTD in the Cerebellum In the cerebellum, long-term depression (LTD) plays a crucial role in motor learning, refining motor strategies, and ensuring precise execution of motor tasks. LTD occurs at the synapses between parallel fibers and Purkinje neurons, facilitated by inputs from climbing fibers. Actors: Parallel fibers: Convey information about the execution of motor tasks programmed by the motor cortex. Climbing fibers: Provide information about the nature of the motor program. Purkinje neurons: Integrate inputs from both parallel and climbing fibers to refine and learn motor commands. Mechanism: 1) Induction of LTD: LTD is induced at the synapse between parallel fibers and Purkinje neurons. Both climbing fibers and parallel fibers are excitatory and release glutamate. o Parallel fiber activity: When parallel fibers release glutamate, it activates metabotropic glutamate receptors (mGluRs) on Purkinje neurons.  o Climbing fiber activity: Concurrently, climbing fibers also release glutamate, which leads to additional intracellular signaling. 2) Activation of mGluRs leads to the activation of phospholipase C (PLC). 3) PLC activity causes the release of calcium from intracellular stores. 4) Climbing fiber activation further increases intracellular calcium levels through the generation of inward calcium currents. 5) The elevated calcium levels activate Protein Kinase C (PKC). 6) PKC phosphorylates various substrates within the Purkinje neuron. 7) PKC-mediated phosphorylation leads to the internalization and removal of AMPA receptors from the postsynaptic membrane. This decreases the responsiveness of Purkinje neurons to glutamate released by parallel fibers, effectively reducing synaptic strength at this site. Functional Significance of LTD in Motor Learning: 1. Refining Motor Commands: o The parallel fibers deliver information about how a motor task was executed, while the climbing fibers provide a reference signal related to the intended motor program. o Purkinje neurons use these two inputs to compare the intended motor command with its actual execution. o By adjusting synaptic strength through LTD, Purkinje neurons can fine-tune motor commands. o This comparison process allows for the correction of errors in motor execution, leading to the perfection and stabilization of motor programs. o Over time, this results in the learning of precise and optimized motor skills. o LTD is an active learning process that enables the cerebellum to adapt motor commands based on feedback. o This adaptability is essential for the smooth and accurate performance of complex motor tasks. Historical Background and Clinical Relevance Research into the mechanisms of memory formation and synaptic plasticity has its roots in both clinical observations and experimental studies. A pivotal case in this research is that of Henry Gustav Molaison (H.M.), who underwent bilateral removal of large portions of his temporal lobes, including the hippocampus, to treat intractable epilepsy. Clinical Observations from H.M.: Seizure Control: The surgery successfully reduced his epileptic seizures. Cognitive Abilities: His IQ remained unaffected, and he retained the ability to form short-term memories and some types of long- term memories. Anterograde Amnesia: H.M. suffered from profound anterograde amnesia, being unable to form new episodic or declarative memories after the surgery. These observations strongly implicated the hippocampus in the formation of new declarative memories, leading to intensive studies of hippocampal function. Discovery of Long-Term Potentiation (LTP) In the 1970s, researchers Timothy Bliss and Terje Lømo provided the first experimental evidence for LTP, a long-lasting enhancement of synaptic strength following high-frequency stimulation. Experimental Setup: Stimulation: Bliss and Lømo stimulated the Schaffer collaterals, the axons projecting from CA3 to CA1 pyramidal neurons. Recording: They recorded the postsynaptic responses in CA1 pyramidal neurons. Observations: 1. High-Frequency Stimulation: o Application of high-frequency stimulation (typically around 12 Hz) to Schaffer collaterals led to a significant and sustained increase in the postsynaptic response of CA1 neurons. o This potentiation could last for over an hour, demonstrating a long-term change in synaptic efficacy. 2. Synapse Specificity: o The potentiation was specific to the synapses that received the high-frequency stimulation. Other pathways synapsing onto the same CA1 neuron did not show increased responses if they were not stimulated. 3. Calcium Dependency: o The induction of LTP was found to be calcium-dependent, requiring an influx of calcium ions into the postsynaptic neuron. Experiments: Initial experiments on LTP were conducted ex vivo, using brain slices from experimental animals. These preparations typically allow for recordings lasting up to 10-12 hours, which limits the observation of long-term effects. In vivo studies enable the observation of LTP over much longer periods, allowing researchers to track changes in individual neurons for days, weeks, or even longer. This capability provides deeper insights into the processes underlying long-term memory. Metaplasticity Plasticity of Plasticity Synaptic plasticity is a fundamental mechanism by which the CNS adapts and learns. However, neurons continuously undergoing short-term and long-term plastic changes face the challenge of avoiding saturation. Metaplasticity, or the "plasticity of plasticity," is a regulatory mechanism that adjusts the threshold for synaptic changes based on the neuron's synaptic history. This ensures that neurons remain adaptable without becoming overly potentiated or depressed. Challenge: If synapses continuously increase in size or number, neurons risk becoming saturated, which would impair their ability to undergo further plastic changes. Conversely, if synapses are excessively pruned, neuronal functionality could be compromised. Metaplasticity helps maintain a balance by modulating the thresholds required for inducing synaptic plasticity: Synaptic History and Threshold Modulation: If a neuron has recently undergone synaptic plasticity (e.g., LTP), subsequent stimuli need to be stronger to induce further plasticity because the threshold for change has increased. Conversely, for LTD, if a neuron has recently experienced synaptic depression, inducing further LTD will require a weaker stimulus due to a lowered threshold. Metaplasticity is crucial for maintaining neurons within a homeostatic range, allowing for continuous adaptation and learning without reaching saturation. There are two primary models to explain this regulation: 1. Threshold Modulation: o LTP: After LTP has occurred, the threshold for further LTP induction is raised, requiring stronger stimuli. o LTD: If the synapse has undergone LTD, the threshold for future LTD may be increased. 2. Moltiplicative Scaling: o Plasticity events can occur according to a scaling factor (F). This factor adjusts based on the neuron's recent activity history: ▪ Active Neuron: If a neuron has been highly active and a new stimulus arrives, the synaptic potentiation at the postsynaptic sites will be minimal (F < 1). This prevents excessive excitation. ▪ Inactive Neuron: If a neuron has been inactive and no recent potentiation or depression has occurred, a new stimulus will result in a more significant synaptic change (F > 1). This enhances the neuron's responsiveness.