Before we start: What is the question? What is the role/contribution of the different subtypes of...
-
date post
20-Dec-2015 -
Category
Documents
-
view
219 -
download
1
Transcript of Before we start: What is the question? What is the role/contribution of the different subtypes of...
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.
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.
Functional Properties of NR1 and NR2
Cull-candy and leszkiewicz, Science STKE, 2004
NR2 NR1Affinity for glutamate Inhibition by Protons
Modulation by Glycine
Potentiation by polyamines
Ca2+ current Inhibition by Zn+2
Channel Kinetics Some kinetics properties (very
unknown)
Dendritic transport, synaptic localization,
trafficking of receptors
Required for release from the ER; might
be important for targeting between
soma and dendrites
Deactivation Kinetics of NR2B subunits
Cull-candy and leszkiewicz, Science STKE, 2004
> Mg2+ sensitive < Mg2+ sensitive
Plasticity in the Hippocampus
Studying Long Term Potentiation (LTP) and Long Term Depression (LTD)
Time (min)
% EPSP
100 %
200 %
Baseline
Stim. Schaffer Collateral at 0.2Hz
CA1
Induction
Stim. Schaffer Collateral at 100Hz, 1sec
CA1
Post- InductionStim. Schaffer Collateral at 0.2Hz
CA1
100Hz
LTP and LTD in CA1HFS 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:
Modifed from Lisman, 1989; Bear and Malenka, 1994.
Ca2+
Presynaptic Postsynaptic
NMDA receptor
HFS
LFS
Support for this model
Intracellular calcium levels
Yang S-N. et al., 1999. J. Neurophysiol.
“LTD” “LTP”
Hippocampal slices, p 11-p22, WC Recording, Photolysis of EGTA
Support for this model
Degree of NMDA receptor activation Amount of calcium
Cummings et al., 1996. Neuron Nishiyama et al., 2000.
Nature
“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…”
BUT… NR2B over-expression:
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.
Induction: association cooperativityspecificity
NMDAR coincidence detection: glutamate & depolarizationGlutamate release- localAMPAR depolarization- small ampl., passive propagation: small spreadBack-propagating AP- big ampl., active propagation: wide-spread
Time, space, co-incidence detection
Timecalcineurin – high affinity, on/offCamIIK- medium affinity, persistent onPKC- medium affinity, on/off
SpaceCa++ via NMDAR- local glutamate, wide-spread voltage unblockCa++ 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!!