BMS 500 Lecture 10

Overview: long-term plasticity in the hippocampus

• Topic of the lecture: cellular and molecular mechanisms of long-term potentiation (LTP) and long-term depression (LTD), including induction, expression, and maintenance, with a focus on NMDA receptor–mediated processes and their role in memory formation.

• Real-world hook: Henry Molayasen (HM) case – bilateral medial temporal lobe (hippocampus) removal cured seizures but abolished ability to form new memories. This iconic case linked the hippocampus to declarative memory and highlighted distinct memory systems:

  • Declarative (explicit) memory: facts/events, hippocampal-dependent.

  • Procedural (nondeclarative) memory: skills and tasks, cerebellum and basal ganglia involvement.

• Memory components introduced:

  • Induction: cellular mechanism to initiate plasticity (what triggers change).

  • Expression: the actual change in synaptic strength (how the change is realized).

  • Maintenance: preserving the change over long timescales (stability of memory).

• Foundational ideas repeated across memory research:

  • Hippocampus critical for forming new declarative memories; retrieval can be hippocampus-independent.

  • Plasticity as a cellular substrate for learning: input specificity, associativity, and coincidence detection.

• Terminology:

  • Hebbian principle: neurons that fire together wire together.

  • Trisynaptic circuit of the hippocampus: entorhinal cortex → perforant path → dentate gyrus granule cells → CA3 → CA1 via Schaffer collateral pathway.

• Key players introduced: NMDA receptors (Mg2+ block, voltage-dependent), AMPA receptors, Ca2+ as a central second messenger, calcium/calmodulin-dependent kinases (CaMKII), calcineurin, TARPs, PSD-95, CREB, PKA, adenylyl cyclase, and basis for new spine formation.

Hippocampal circuitry and the canonical site of plasticity

• Trisynaptic circuit in the hippocampus:

  • Entorhinal cortex → perforant path synapses onto dentate gyrus granule cells.

  • Granule cells → CA3 via mossy fibers; CA3 → CA1 via Schaffer collaterals.

  • Primary site for LTP/LTD studies: CA3–CA1 synapse (Schaffer collateral pathway).

• Focus for LTP/LTD mechanisms: CA3 → CA1 synapse (Schafer collaterals).

• In vivo relevance: LTP can be observed after a single high-frequency train (tetanic stimulation) lasting up to days and even up to a year in some models.

Induction of LTP: key principles and evidence

• Two essential features of induction:

  • Specificity: only activated synapses during induction show potentiation; nearby inactive synapses do not potentiated.

  • Associativity: stimulation of one strong pathway can strengthen another pathway when both are activated together or when a weak input is paired with postsynaptic depolarization.

• Coincidence detection: induction requires two events to coincide at a synapse:

  • Presynaptic glutamate release (synaptic activity).

  • Postsynaptic depolarization (to relieve Mg2+ block on NMDA receptors).

• NMDA receptor as biophysical coincidence detector:

  • At resting membrane potential, NMDA receptors are blocked by Mg2+; AMPA receptors mediate current.

  • Upon depolarization, Mg2+ block is relieved, allowing Ca2+ influx through NMDA receptors when glutamate is present.

  • Calcium entry is the trigger for downstream signaling that leads to LTP induction.

• Classic induction experiment (Bliss & Lomo, 1973, in the Schaffer collateral pathway):

  • Two independent presynaptic inputs to CA1 (pathway 1 and pathway 2).

  • Baseline: low-frequency stimulation (to measure EPSP).

  • Tetanic stimulation (≈ $100 ext{ Hz}$ for $1 ext{ s}$) of pathway 1.

  • Post-tetanus: stimulation at low frequency shows a sustained increase in EPSP for pathway 1, but not pathway 2 (pathway 2 remains unchanged).

  • Result: LTP is input-specific to the pathway that experienced tetanic stimulation.

• Quantitative readouts from early experiments:

  • After tetanus, EPSP amplitude can rise to roughly $3 imes$ baseline for the stimulated pathway (e.g., from 100% to ~300%).

  • Potentiation is stable over long timescales: minutes to hours; in vivo studies show persistence up to $365 ext{ days}$ in some models.

• NMDA receptor involvement in induction (pharmacology):

  • NMDA receptor antagonist APV (or AP5) blocks induction of LTP when present during the induction window.

  • If APV is applied only after induction, LTP can still be expressed, indicating NMDA receptors are crucial for induction, not maintenance/expression per se.

• Consequence: LTP induction requires NMDA receptor activation and postsynaptic depolarization; Ca2+ entry through NMDA receptors activates downstream signaling that induces synaptic strengthening.

Biophysical mechanisms of the induction signal (Ca2+ entry and downstream cascades)

• Calcium as the central second messenger:

  • Calcium influx through NMDA receptors activates calmodulin (CaM).

  • Ca2+/CaM activates Ca2+/calmodulin-dependent protein kinase II (CaMKII).

  • CaMKII activation leads to autophosphorylation, creating a sustained signal beyond the transient Ca2+ rise.

• CaMKII is the pivotal kinase for LTP expression in the hippocampus:

  • Activation of CaMKII is required for LTP expression; PKC is another possible pathway (via metabotropic receptors), but the CaMKII arm is the canonical hippocampal LTP pathway.

• Two complementary expression mechanisms that increase postsynaptic strength: 1) Rapid trapping of existing AMPA receptors in the postsynaptic density (PSD) via phosphorylation of TARPs (AMPA receptor auxiliary subunits) that link AMPA receptors to PSD-95 in the postsynaptic spine.

  • Mechanistic gist: phosphorylated TARPs tether AMPA receptors to the PSD where glutamate receptors are most effective.
    2) Slower, CaMKII- and Ca2+-dependent insertion of additional AMPA receptors into the postsynaptic membrane via SNARE/synaptotagmin-related vesicle fusion.

  • End result: increased postsynaptic AMPA receptor density and signaling at the activated synapses.

• Role of TARPs and PSD-95 (synaptic scaffolding):

  • TARPs accompany AMPA receptors and, when phosphorylated, promote receptor trapping at the PSD-95 scaffold.

  • PSD-95 defines the postsynaptic density region where receptor trapping occurs.

• Silent synapses and developmental relevance:

  • Some synapses contain NMDA receptors but lack functional AMPA receptors (silent at negative potentials).

  • Depolarization relieves Mg2+ block and can recruit AMPA receptors to become active, revealing an inward current.

  • In development, silent synapses can be recruited during plasticity, contributing to network refinement.

Expression of LTP: post-synaptic changes that solidify strength

• After induction, LTP expression reflects an increased number of postsynaptic AMPA receptors: more channels available for glutamate signaling at the synapse.

• This is a postsynaptic phenomenon, contrasting with some presynaptic forms of plasticity (e.g., changes in vesicle release probability) discussed earlier in class.

• The expression phase links transient Ca2+ signals to lasting changes in synaptic efficacy via receptor trafficking and changes in receptor density.

Maintenance of LTP: sustaining changes over time

• Maintenance requires protein synthesis and gene expression:

  • Blocking protein synthesis around the 8-hour timescale can disrupt maintenance of LTP, indicating translation-dependent stabilization.

  • Translation-independent early phases give way to transcription-driven changes that solidify synaptic architecture.

• CREB-mediated transcription and spine remodeling:

  • Calcium/CaM activates signaling that leads to CREB (cAMP response element-binding protein) phosphorylation and transcription of plasticity-related genes.

  • Protein kinase A (PKA) can be activated via adenylyl cyclase to increase cAMP, further promoting CREB activity.

  • New gene expression supports structural changes, including spine growth and stabilization.

• Spine remodeling as a substrate of maintenance:

  • LTP-associated spines often become mushroom-shaped (stable, larger spines) and can be preserved over time.

  • New spines can form in response to learning-related activity, creating permanent changes in connectivity.

• Summary of maintenance pathway:

  • Ca2+ entry → CaMKII activation → initial AMPA receptor trafficking/anchoring → CaMKII-driven gene transcription via CREB → spine remodeling and new synapse formation → long-term stability of potentiation.

Long-term depression (LTD): weakening synapses and its mechanism

• LTD is the long-term weakening of synapses, typically elicited by prolonged, low-frequency stimulation (LFS).

• Specificity is preserved: LTD affects the activated synapses.

• NMDA receptor involvement in LTD, but with a different calcium signature:

  • Calcium entry through NMDA receptors during LTD is smaller and more prolonged than in LTP.

  • The resulting calcium profile preferentially activates phosphatases (not kinases).

• Key phosphatase: calcineurin (PP1).

  • Calcium/calmodulin activates calcineurin, which dephosphorylates target proteins and promotes AMPA receptor endocytosis.

  • Dephosphorylation reduces AMPA receptor surface expression, leading to decreased synaptic strength.

• End result: LTD is achieved by removal/endocytosis of AMPA receptors, reversing the LTP-associated postsynaptic changes.

• Conceptual takeaway: LTD is the counterpart to LTP, with NMDA receptor activity and calcium signaling guiding the balance between phosphorylation (strengthening) and dephosphorylation (weakening).

Calcium as the central messenger and the general takeaways

• Calcium