GABAergic interneuron origin of schizophrenia pathophysiology

Abstract

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.

Figure 1. The GABAergic neuronal dysfunction hypothesis of schizophrenia pathophysiology

According to this hypothesis, precipitating factors may include any combination of genetic disposition, maternal infection or malnutrition, and obstetric complications. When these insults lead to NMDAR hypofunction of cortical interneurons, especially parvalbumin (PV)-containing fast-spiking neurons, during development, pathophysiological phenotypes (cortical disinhibition, impaired oscillatory activity, dopaminergic dysregulation, and oxidative stress) may arise, precipitating the emergence of major schizophrenia-like symptoms after adolescence.

Figure 2. Mechanism by which NMDAR deletion in cortical parvalbumin (PV) neurons could alter cortical activity, leading to the emergence of subcortical dopamine hyperactivity in mice

NMDAR deletion in cortical PV neurons down-regulates their GABA synthesis and release, which not only results in cortical disinhibition but also impairs the synchronized activity of principal neurons. This may reduce the cortical output to VTA and thereby increases dopamine activity in the nucleus accumbens. DA = dopamine, mPFC = medial prefrontal cortex, VTA = ventral tegmental area. Diagram is modified from Lewis and Gonzalez-Burgos 2006.