22.LTPs

Neurophysiology XXII: Long-term Synaptic Plasticities

22.1 Long-term Potentiation

  • Hippocampal Formation: Key brain region for learning and memory; significant in the case study of Patient H.M. (Scoville & Milner, 1957).

  • High-Frequency Stimulation:

    • Discovered by Bliss and Lomo (1973).

    • A brief episode (1 second) of high-frequency stimulation (around 100 Hz) induces lasting increases in synaptic transmission strength.

  • EPSP Measurement:

    • EPSPs from CA1 pyramidal neurons show constant amplitude with low-frequency stimulation (0.1 Hz).

    • High-frequency stimulation (100-400 Hz for 1-3 seconds) leads to long-term potentiation (LTP).

22.2 Induction of LTP

  • Typical Experiment:

    • Record synaptic response at low frequency for 10-15 minutes as a baseline.

    • Apply high-frequency stimulation (e.g., 100 Hz for 3 seconds).

    • Post-tetanic potentiation observed in first few minutes; prolonged response amplitude increase for hours/days.

  • Mechanisms:

    • LTP observed throughout mammalian brain, but mechanisms vary.

    • Activated primarily in tetanized pathway; Ca2+ dependent.

    • Blocked by removing extracellular Ca2+, using Ca2+ chelators (BAPTA, EGTA), AMPA receptor antagonists, and NMDA receptor blockers.

22.3 Expression of LTP

  • Initiation:

    • Triggered by NMDA receptor opening and increased intracellular Ca2+.

    • LTP is Hebbian; requires presynaptic and postsynaptic activity.

  • NMDA Receptor Role:

    • Acts as a Hebbian coincidence detector.

    • Mg2+ blocks NMDA receptors under low depolarization; tetanic stimulation relieves this block, allowing Ca2+ entry.

  • Additional Pathways:

    • Metabotropic glutamate receptors (mGluR) can stimulate IP3 metabolism, releasing Ca2+ from intracellular stores.

    • mGluR agonist (ACPD) shows potential for LTP under specific conditions.

22.4 Long-term Depression (LTD; Hippocampal and Neocortex)

  • Concept: Synaptic plasticity not only potentiates but can depress.

  • Induction of LTD:

    • Low-frequency stimulation (~1 Hz for ~15 minutes) depresses AMPA-mediated responses, NMDA-dependent.

  • Calcium Dynamics:

    • Differentiates LTP from LTD; selective elevation in Ca2+ concentration activates protein phosphatases for LTD.

22.5 Spike Timing Dependent Plasticity (STDP)

  • Timing Effects:

    • Enhancement or depression occurs based on timing of synaptic input relative to postsynaptic spikes.

    • Pre-spike transmitter release leads to LTP; post-spike results in LTD.

  • Mechanism:

    • NMDA receptor dependency; selective backpropagating spikes amplify Ca2+ influx.

22.6 Cerebellar LTD

  • Cerebellum Function:

    • Involved in motor control; principal neuron is Purkinje cell.

    • Excitatory inputs from parallel fibers and single climbing fiber connection.

  • Induction Mechanism:

    • Coinciding stimulation of parallel fibers and climbing fibers leads to LTD in Purkinje cells.

    • Mechanism involves protein kinase C activation and AMPA receptor downregulation.

Associative Learning and Cerebellar LTD

  • Eyeblink Reflex:

    • Reflex arc simulates muscle activation and excitatory signals to the inferior olive.

    • Stimulation typically inhibited by Purkinje cells, but LTD can weaken this inhibition, enhancing the reflex to conditioned stimuli (e.g., sound).