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Before we start:. What is the question? What is the role/contribution of the different subtypes of NMDA glutamate receptor to plasticity in the brain? Why is it interesting? NMDA receptors play an important role in many forms of synaptic plasticity.

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  1. Before we start: • What is the question? • What is the role/contribution of the different subtypes of NMDA glutamate receptor to plasticity in the brain? • Why is it interesting? • NMDA receptors play an important role in many forms of synaptic plasticity. • NMDA receptors are important for cell survival and cell death (ischemia, excess glutamate) • NMDA receptor composition changes during development and it has been proposed to be one of the main regulators of the critical period. • The developmental switch between NR2A and NR2B can be modulated by experience.

  2. Glutamate Receptors: NMDA-sensitive • Tetramers with the following subunits: • NR1 (always 2) • 8 splice variants. • Glycine binding site. • The different splice variants differ in their conductances, their affinity for glycine, etc. • NR2 (always 2) • Glutamate binding site. • Need NR1 to form functional receptors • 4 genes. (NR2A, NR2B. NR2C, NR2D) • Only NR2A and NR2B are expressed in the forebrain. • NR2A and NR2B are developmentally regulated, with NR2B starting to decrease after a few weeks. • Very little is known about the proteins that each subunit interacts with.

  3. NMDAR Receptors: Adult distribution of NR2 Nakanishi, S., 1992., Science

  4. Functional Properties of NR1 and NR2 Cull-candy and leszkiewicz, Science STKE, 2004

  5. Deactivation Kinetics of NR2B subunits > Mg2+ sensitive < Mg2+ sensitive Cull-candy and leszkiewicz, Science STKE, 2004

  6. Baseline % EPSP Stim. Schaffer Collateral at 0.2Hz 200 % CA1 100 % Induction Time (min) Stim. Schaffer Collateral at 100Hz, 1sec CA1 Post- Induction Stim. Schaffer Collateral at 0.2Hz CA1 Plasticity in the Hippocampus Studying Long Term Potentiation (LTP) and Long Term Depression (LTD) 100Hz

  7. Ca2+ LTP and LTD in CA1 • HFS of the Schaffer collateral fibers leads to LTP in CA1. • LFS of the Schaffer collateral fibers leads to LTD in CA1. • These changes in synaptic strength depend on: • Intracellular calcium. • NMDA receptors. Simple Model: Postsynaptic Presynaptic HFS LFS NMDA receptor Modifed from Lisman, 1989; Bear and Malenka, 1994.

  8. Support for this model Hippocampal slices, p 11-p22, WC Recording, Photolysis of EGTA • Intracellular calcium levels “LTD” “LTP” Yang S-N. et al., 1999. J. Neurophysiol.

  9. Support for this model • Degree of NMDA receptor activation  Amount of calcium Cummings et al., 1996. Neuron Nishiyama et al., 2000. Nature

  10. NR2B KO NR2A KO

  11. BUT… NR2B over-expression: “Genetic enhancement of learning and memory in mice” Tang et al., Nature 1999. “NR2B expression is downregulated during the period of transition between juvenile and adult, correlating with the gradual shortening of the EPSP duration through the NMDA channel. This could decrease NMDA-mediated plasticity, and perhaps explain decreased memory performance in adult animals…”

  12. “Smart Mice”: Over-expression of NR2B Enhanced Novel Object Recognition Tang et al., 1999. Nature.

  13. Selective block of NR2A % block current 2B 2A In oocytes In hippocampal slices

  14. NR2A X LTD LTP HFS LFS

  15. NR2B X LTD (1XLFS) LTP (1XHFS) HFS LFS

  16. Conclusions: [Ca++] • 0.1uM Ca++ (resting) too low for both calcineurin & CamIIK – stable release • ~1uM Ca++ (LFS=1-5 Hz) – calcineurin: LTD • >5uM Ca++ (HFS=>Hz) – calcineurin + CamIIK… CamIIK out-competes: LTP Molecular ID of NR2 NR2A necessary for LTP, not LTD. • NR2B necessary for LTD, not LTP. • Reduction of NR2B during development could explain increased difficulty in inducing LTD.

  17. who or where??? “Spillover” during HFS

  18. Induction: association cooperativity specificity Time, space, co-incidence detection NMDAR coincidence detection: glutamate & depolarization Glutamate release- local AMPAR depolarization- small ampl., passive propagation: small spread Back-propagating AP- big ampl., active propagation: wide-spread Time calcineurin – high affinity, on/off CamIIK- medium affinity, persistent on PKC- medium affinity, on/off Space Ca++ via NMDAR- local glutamate, wide-spread voltage unblock Ca++ via IP3- local glutamate (mGluR) Ca++ via VG-CC- wide-spread Ca++ AP Spill-over (2A/2B in synapse; 2B extra-synaptic) NO- trans-cellular, on/off,intermed. distance- retrograde transmitter!!

  19. Na+ channels NOS AP

  20. tag Specificity - synaptic tagging

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