Stress-Evoked Tyrosine Phosphorylation of Signal Regulatory Protein α Regulates Behavioral Immobility in the Forced Swim Test

Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRP alpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRP alpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRP alpha in the brain of wild-type mice through activation of Src family kinases. The SIRP alpha ligand CD47 was important for such SIRP alpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kv beta 2 was regulated by SIRP alpha. Thus, tyrosine phosphorylation of SIRP alpha is important for regulation of depression-like behavior in the response of the brain to stress.