Fig. 3

Dual NMDAR hypofunction model for schizophrenia pathophysiology. Accumulating evidence from genetic and pharmacological studies lend support for spatially and temporally dissociated NMDAR hypofunction events in schizophrenia pathophysiology. The first NMDAR hypofunction occurs in cortical GABA neurons, including PV neurons, during early postnatal development, impairing the cortical circuitry maturation and leading to a variety of fast-spiking neuron-associated abnormalities, including gamma band synchrony deficits, oxidative stress increase, dopamine dysregulation, and disinhibition of pyramidal neurons. These abnormalities could contribute to the emergence of positive, negative and cognitive symptoms. Moreover, the E/I balance increase eventually elicits glutamate spillover during the prodromal period or later, which could produce a second NMDAR hypofunction in pyramidal neurons in response to low level but cumulative excitotoxicity. NMDAR hypofunction in pyramidal neurons may be responsible for spine density alteration of cortical pyramidal cells, which could also contribute to cognitive and negative symptoms as the disease progresses. Therefore, both types of NMDAR hypofunction may contribute to the schizophrenia pathophysiology. It is unclear when the first NMDAR hypofunction ends and the second hypofunction starts (shown by dotted lines). The cause of the first NMDAR hypofunction remains to be determined (but see text)