Activity-regulated somatostatin expression reduces dendritic spine density and lowers excitatory synaptic transmission via postsynaptic somatostatin receptor 4.

Neuronal activity regulates multiple aspects of the morphological and functional development of neural circuits. One mechanism by which it achieves this is through regulation of gene expression. In a screen for activity-induced genes, we identified somatostatin (SST), a neuropeptide secreted by the SST subtype of interneurons. Using real time quantitative PCR and ELISA, we showed that persistent elevation of neuronal activity increased both the gene expression and protein secretion of SST over a relatively prolonged time course of 48 h. Using primary hippocampal neuronal cultures, we found that SST treatment for 1 day significantly reduced the density of dendritic spines, the morphological bases of excitatory synapses. Furthermore, the density of pre- and postsynaptic markers of excitatory synapses was significantly lowered following SST treatment, whereas that of inhibitory synapses was not affected. Consistently, SST treatment reduced the frequency of miniature excitatory postsynaptic currents, without affecting inhibition. Finally, lowering the endogenous level of SST receptor subtype 4 in individual hippocampal pyramidal neurons significantly blocked the effect of SST in reducing spine density and excitatory synaptic transmission in a cell autonomous fashion, suggesting that the effect of SST in regulating excitatory synaptic transmission is mainly mediated by SST receptor subtype 4. Together, our results demonstrated that activity-dependent release of SST reduced the density of dendritic spines and the number of excitatory synapses through postsynaptic activation of SST receptor subtype 4 in pyramidal neurons. To our knowledge, this is the first demonstration of the long term effect of SST on neuronal morphology.