Figure 2.
A working model of glutamate actions at network synapses in monkey dorsolateral PFC. A. Stimulation of NMDA receptors in the synapse mediates network inputs. B. In contrast, stimulation of perisynaptic mGluR1/5 provides negative feedback via Gq signaling. For both A and B, examples of genetic insults in schizophrenia are shown in navy blue; dysbindin regulates glutamate release; DAAO (D-amino acid oxidase) regulates levels of the NMDA modulator, D-serine, while neuregulin 1 regulates NMDA receptor structure and function at the synapse [79]. The actions of soluble Aβ in AD are shown in magenta; Aβ internalizes NMDA receptors in the presence of α7 nicotinic receptors, and stimulates mGluR1. C. Layer V pyramidal cell connections in rat PFC show larger NMDA currents than those in primary visual cortex (V1) in response to a sequence of 10 stimulating pulses and a recovery pulse. Figure courtesy of W.J. Gao with the permission of PNAS USA [9]. D. The NMDA current in rat PFC is increased in the presence of apamin, a selective blocker of SK channels. Figure courtesy of E.S. Faber [16]. E. RGS4 in PFC spines is typically found perisynaptically (double arrowheads point to the synapse) in monkey PFC, where it is strategically positioned to inhibit mGluR1/5-Gq signaling (adapted from [19]). RGS4 is shown in navy blue in B to highlight its reduced expression in PFC in patients with schizophrenia. RGS4 levels are also reduced in AD. F. Blockade of SK channels in rat PFC with apamin, or of IP3-induced Ca2+ release using xestospongin C (XeC), improves working memory performance compared to vehicle (veh) control infusion. Results represent mean ± SEM percent correct. Adapted from [20].