Hypofunction of N-methyl-D-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes-from molecular and physiological to behavioral-resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults-including excitotoxicity and oxidative stress-might help to explain their significant contribution to the development of schizophrenia.

Summary Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity’s net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5–6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation.

The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti-N-methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down-regulation of cell surface N-methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when N-methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from N-methyl-d-aspartate receptor antagonist and autoantibody models, postmortem studies on N-methyl-d-aspartate receptor subunits, as well as the global and cell-type-specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of N-methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that N-methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of N-methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct N-methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for N-methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring N-methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance.

Calcium-dependent activator protein for secretion 2 (CAPS2) is a dense-core vesicle-associated protein that is involved in the secretion of BDNF. BDNF has a pivotal role in neuronal survival and development, including the development of inhibitory neurons and their circuits. However, how CAPS2 affects BDNF secretion and its biological significance in inhibitory neurons are largely unknown. Here we reveal the role of CAPS2 in the regulated secretion of BDNF and show the effect of CAPS2 on the development of hippocampal GABAergic systems. We show that CAPS2 is colocalized with BDNF, both synaptically and extrasynaptically in axons of hippocampal neurons. Overexpression of exogenous CAPS2 in hippocampal neurons of CAPS2-KO mice enhanced depolarization-induced BDNF exocytosis events in terms of kinetics, frequency, and amplitude. We also show that in the CAPS2-KO hippocampus, BDNF secretion is reduced, and GABAergic systems are impaired, including a decreased number of GABAergic neurons and their synapses, a decreased number of synaptic vesicles in inhibitory synapses, and a reduced frequency and amplitude of miniature inhibitory postsynaptic currents. Conversely, excitatory neurons in the CAPS2-KO hippocampus were largely unaffected with respect to field excitatory postsynaptic potentials, miniature excitatory postsynaptic currents, and synapse number and morphology. Moreover, CAPS2-KO mice exhibited several GABA system-associated deficits, including reduced late-phase long-term potentiation at CA3-CA1 synapses, decreased hippocampal theta oscillation frequency, and increased anxiety-like behavior. Collectively, these results suggest that CAPS2 promotes activity-dependent BDNF secretion during the postnatal period that is critical for the development of hippocampal GABAergic networks.dense-core vesicles | brain-derived neurotrophic factor | GABAergic synapse