Src inhibition reduces NR2B surface expression and synaptic plasticity in the amygdala.
The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src tyrosine kinase has not been investigated. We have synthesized a Src-derived peptide, Tat-Src (40-58), that crosses the blood-brain barrier following injection and accumulates intracellularly. Tat-Src (40-58) blocks the interaction of Src with NMDA receptors. Following injection, mice demonstrate impaired amygdala-dependent cued fear conditioning, as well as impairments in an amygdala-dependent nonassociative social recognition task. The Src inhibitor decreased NR2B phosphorylation in amygdala tissue and reduced NR2B surface expression in cultured amygdala neurons with a concomitant reduction in NMDA multimer-containing dendritic puncta. In addition, preincubation of this inhibitory peptide blocked amygdalar long-term potentiation in the lateral to basolateral pathway in vitro. These results indicate that Src is a key regulator of NMDAR trafficking in the amygdala. Furthermore, Src-dependent phosphorylation of NR2B supports amygdala plasticity and amygdalar-dependent learning.
Sinai
Laleh
L
Mount Sinai Hospital Research Institute, Toronto, Ontario M5G 1X5, Canada. sinai@lunenfeld.ca
Duffy
Steven
S
Roder
John C
JC
D000161:Acoustic Stimulation / Q000009:adverse effects; D000679:Amygdala / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000187:drug effects; D007859:Learning Disabilities / Q000209:etiology / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014828:Vocalization, Animal / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; C121001:NR2B NMDA receptor; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases