Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.
Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.
Migaud
M
M
Centre for Genome Research, University of Edinburgh, UK.
Charlesworth
P
P
Dempster
M
M
Webster
L C
LC
Watabe
A M
AM
Makhinson
M
M
He
Y
Y
Ramsay
M F
MF
Morris
R G
RG
Morrison
J H
JH
O'Dell
T J
TJ
Grant
S G
SG
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D018390:Gene Targeting; D051528:Guanylate Kinases; D006624:Hippocampus / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007858:Learning / Q000502:physiology*; D007859:Learning Disabilities / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D051528:Guanylate Kinases