Modulation of glutamatergic synaptic transmission and plasticity by sigma receptor type 1 in the CA1 region of the hippocampus

Abstract

The sigma receptor (sigmaR), once considered a subtype of opioid receptor, is now described as a distinct pharmacological entity. sigma1Rs are thought to be implicated in neuropsychiatric disorders such as schizophrenia, depression as well as in learning and memory. The modulation of N-methyl-D-aspartate receptor (NMDAR) by the sigma1R has been extensively documented; however, the mechanism through which the sigma1R modulates the NMDAR has been a mystery for almost two decades. Here, I report that sigma1R activation increases NMDAR responses and long-term potentiation (LTP) by blocking a small conductance Ca2+-activated K+ current (SK channels) known to shunt NMDAR responses. Therefore, the blockage of SK channels and the resulting increased Ca2+ influx through the NMDAR enhances NMDAR responses and LTP. These results emphasize the importance of the sigma1R as a post-synaptic regulator of synaptic transmission.