CONCEPTS IN NEUROBIOLOGY

Mechanisms of Neural Plasticity

FALL SEMESTER 2010

Introduction to terms and concepts of synaptic plasticity

Big Question: What are the mechanisms underlying learning and memory?

Background: Brenda Milner, founder of cognitive psych field, H.M., suggested hippocampus as place to start. Bliss and Lomo 1973. Pre or post? Role of NMDA-R, Ca++, PO4ation and insertion of AMPA-R. Visual and barrel cortex have also become important model systems for studying mechanisms underlying changes in strength of neural connections (synapses). In this case there is a critical period for maximal changes.

Methods: Slice (in vitro) electrophysiology, pharmacology, quantal analysis usingpatch clamp, biochemistry

I. Types of plasticity

  • Short-term
  • presynaptic calcium accumulation  changes in probability of transmitter release
  • PPF/PPD
  • Paired pulse depression PPD < 20 ms
  • Mechanisms
  • depletion of readily releasable pool of vesicles
  • inactivation of sodium or calcium channels
  • Paired pulse facilitation PPF 20-500 ms
  • Mechanisms
  • excess calcium from 1st spike
  • changes in presynaptic phosphoproteins
  • Post-tetanic Potentiation PTP produced by trains of stimuli (200 ms – 5 sec @ 10-200 Hz)
  • Mechanism
  • enhancement of transmitter release
  • due to Ca++ buildup
  • Post-tetanic Depression PTD
  • Mechanisms
  • Depletion of readily releasable pool of vesicles
  • Neuromodulators
  • Receptor desensitization
  • Use-dependent

II. Presynaptic changes

  • presynaptic, metabotropic G-protein-coupled receptors
  • retrograde messengers
  • NO
  • BDNF
  • Endocannabinoids
  • Anandamide
  • 2-AG

III. LTP/LTD

  • Properties
  • Cooperative
  • Associative (a la Pavlov)
  • Input-specific
  • High-freq stim  LTP
  • Low-freq stim  LTD
  • Thresholds depend on Ca++ levels. BCM set point, Ca++ sensors
  • STDP The percentage change in the synaptic strength (EPSC amplitude) after repetitive retinal stimulation was plotted against the onset time of the retinal stimulation relative to the peak of the action potential initiated in the tectal cell. Data shown are for experiments in which spiking of the tectal neuron was initiated by either a suprathreshold input or a group of coactive inputs (filled circles) or by injection of a depolarizing current (open circles) in a tectal neuron (from Zhang et al., 1998; see link for review)
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  • NMDAR-dep LTP
  • Mechanism
  • autophosphorylation of CamKII
  • activation of protein kinases
  • phosphorylation of AMPAR
  • receptor trafficking: insertion/modification of AMPAR at PSD-95
  • Maintenance
  • synaptic tagging
  • NMDAR-dep LTD
  • Mechanism
  • Ca++-dep phosphatase activation (calmodulin-dep phosphatase calcineurin)
  • dephosphorylation of AMPAR
  • receptor trafficking: removal of AMPAR from membrane
  • mossy fiber LTP is presynaptic and Ca++-dependent
  • mGluR-dep LTD in cerebellum via PKC
  • eCB-LTD at inhibitory synapses in hippocampus
  • Homeostatic plasticity
  • synaptic scaling
  • Metaplasticity (plasticity of plasticity mechanisms)

References

  • Lüscher C, Malenka RC. (2012) NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol. 2012 Jun 1;4(6). doi:pii: a005710. 10.1101/cshperspect.a005710.
  • Malenka RC, Bear MF. (2004) LTP and LTD: an embarrassment of riches. Neuron44(1):5-21.

R Miles, J-C Poncer, D Fricker, X Leinekugel (2005) The birth (and adolescence) of LTP. (Mini-review of classic papers) J Physiol. 568(Pt 1): 1–2.

  • Raymond CR. (2007) LTP forms 1, 2 and 3: different mechanisms for the ‘long’ in long-term potentiation. Trends Neurosci 30(4):167-175.
  • Citri A, Malenka RC. (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 33(1):18-41.
  • Lee HK, Kirkwood A. AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex. Semin Cell Dev Biol. 2011. doi:10.1016/j.semcdb.2011.06.007
  • Habib D, Dringenberg HC.Low-frequency-induced synaptic potentiation: a paradigm shift in the field of memory-related plasticity mechanisms? Hippocampus. 2010 Jan;20(1):29-35.
  • K. Deisseroth, H. Bito, H. Schulman, R.W. Tsien A molecular mechanism for metaplasticity. Current Biology 1995, 5:1334-1338. 2330-2376.
  • Kumar A. Long-Term Potentiation at CA3-CA1 Hippocampal Synapses with Special Emphasis on Aging, Disease, and Stress. Front Aging Neurosci. 2011;3:7