Cortical dysfunction in schizophrenia has been attributed to both inhibitory GABA and excitatory glutamate neurotransmission. Abnormalities in cortical GABA neurons have been observed primarily in the subset of GABA interneurons that contain the calcium-binding protein parvalbumin (PV). The glutamatergic dysfunction is suspected primarily because reducing glutamate neurotransmission at the NMDA receptors produces behavioral deficits that resemble symptoms of schizophrenia. These two mechanisms have been generally treated as separate conjectures when conceptualizing theories of schizophrenia. The paper by Cunningham et al. demonstrates that, in fact, disruptions in PV positive cortical GABA neurons and blockade of NMDA receptors produce similar disruptions to the function of cortical networks.

The authors used lysophosphatidic acid 1 receptor (LPA-1)-deficient mice which, they argue, are a relevant model of schizophrenia because these animals display sensorimotor gating deficits, a critical feature of schizophrenia. They demonstrate that, similar to schizophrenia, the number of PV positive GABA neurons is significantly reduced in LPA-1-deficient mice. Furthermore, the γ frequency network oscillation disruptions they observe in these animals are similar to those seen in wild-type mice treated with the NMDA antagonist ketamine. (γ oscillations have been associated with sensory processing and deficits in γ rhythm generation have been reported in patients with schizophrenia during performance of sensory processing tasks.) The disruptive effect of ketamine on γ oscillations was mediated by a decrease in the output of fast-spiking GABA interneurons causing a disinhibition (i.e., increased firing) of glutamate neurons. These findings are significant because they suggest that cortical NMDA hypofunction may cause the reported GABA interneuron deficits in schizophrenia.

View all comments by Bita Moghaddam

Animal models of schizophrenia and other psychiatric disorders are receiving increasing interest, as they provide useful tools to test possible pathophysiological scenarios. Some models have been tested with a wide array of approaches and many others continue to develop. If one focuses on possible cortical alterations, a critical issue emerging from many different lines of research using several different models is the apparent contradiction between the hypo-NMDA concept and the data suggesting a loss of cortical interneurons. Is there a hypo- or a hyperactive cortex?

This conundrum has been present since earlier days in the postmortem and clinical research literature, but with the advent of more refined animal models, it may be time to provide a possible way in which these discrepant sets of data can be reconciled. Whether this was the authors’ intention or not, the article by Cunningham and colleagues is an excellent step in that direction. This study used mice deficient in lysophosphatidic acid 1 receptor, a manipulation that reduced the GABA and parvalbumin-containing interneuron population by about 40 percent and disrupted γ (rapid) oscillations in the entorhinal cortex. A key element in this study was the finding that a similar alteration in rapid cortical oscillations was observed with the noncompeting NMDA antagonist ketamine. There is a large body of evidence indicating that interneurons (in particular, the fast-spiking type that include parvalbumin-positive neurons) are critical for synchronization of fast cortical oscillatory activity. As fast oscillations can be envisioned as phenomena with deep impact on cognitive functions, these findings may have bearing on possible pathophysiological scenarios underlying cognitive deficits in schizophrenia. This article does provide a strong indication that antagonism of NMDA receptors may selectively target cortical interneurons. This is in agreement with the work of Bita Moghaddam, who has shown that noncompeting NMDA antagonists can indeed increase pyramidal cell firing and glutamate levels in the prefrontal cortex. Thus, it is conceivable that psychotomimetic agents such as PCP or ketamine exert their cognitive effects by impairing interneuronal activity, hampering the fine-tuning of pyramidal cell firing that is expressed as fast cortical oscillations.

View all comments by Patricio O'Donnell