Multiple long-range inputs evoke NMDA currents in prefrontal cortex fast-spiking interneurons

Several aspects of schizophrenia can be mimicked acutely in healthy human volunteers via administration of NMDA glutamate receptor (NMDAR) antagonists. As these agents decrease firing rates in prefrontal cortical (PFC) GABAergic fast-spiking interneurons (FSI) in animal studies, a leading hypothesis on schizophrenia pathophysiology is that NMDAR in FSI are impaired. However, whole-cell recordings of FSI in slices of adult mouse PFC revealed limited amounts of NMDAR-mediated current. Since those studies used local electrical stimulation to activate a heterogeneous set of synaptic inputs to the recorded cell, it is unclear whether specific afferent inputs may preferentially drive NMDAR responses in FSI. Here, we expressed opsins in discrete brain regions projecting to the PFC in adult male mice, enabling light-activation of defined, homogenous sets of long-range inputs to FSI and pyramidal neurons recorded in slices containing medial PFC (mPFC). Stimulation of axons originating from either the contralateral mPFC, ventral hippocampus, or mediodorsal thalamus evoked NMDAR-mediated currents in the vast majority of FSI and in all pyramidal neurons recorded. The observation that multiple long-range inputs to mPFC FSI elicit NMDAR currents suggests that the NMDAR-hypofunction model of schizophrenia may still imply a loss of interneuron inputs, but the sources of reduced excitation may originate from sites upstream of the PFC.