Investigating acute N-methyl-D-aspartate (NMDA) receptor hypofunction and novel therapeutic targets with an aim to understanding the cognitive deficits associated with schizophrenia

Abstract

Schizophrenia is a neuropsychiatric disorder characterized by significant cognitive deficits, including impairments in working memory, selective attention, and executive function. The anterior cingulate cortex (ACC) and hippocampus are critical regions involved in these cognitive processes. N-methyl-D-aspartate (NMDA) receptor hypofunction has been proposed as a key mechanism underlying the cognitive impairments observed in schizophrenia. This hypofunction is associated with aberrant beta (20-30 Hz) and gamma (30-80 Hz) oscillations, as well as impaired working memory in patients. Additionally, increased neuroinflammation and a loss of fast spiking parvalbumin (PV)+ interneurons have been documented in post-mortem brain tissue from patients with schizophrenia. However, the relationship between cognitive dysfunction and neuroinflammation in schizophrenia remains poorly understood. This study aimed to explore the effects of NMDA receptor hypofunction on beta and gamma oscillations in the ACC and hippocampus of rat brain slices, utilizing phencyclidine (PCP) as an NMDA receptor antagonist to model schizophrenia-related cognitive deficits. In vitro electrophysiological recordings demonstrated that PCP had no significant impact on gamma oscillations in the CA3 region of the hippocampus. However, in the ACC, PCP significantly increased beta oscillations and induced a shift from gamma to beta frequencies. These aberrant beta oscillations were normalized by activating metabotropic glutamate 2 (mGlu2) receptors and could be blocked by the sigma-1 (σ1) receptor antagonist, NE-100. Immunofluorescence microscopy was used to assess changes in interneuron populations (PV+ and somatostatin; SST+), perineuronal net (PNN) expression, and neuroinflammatory markers (microglia and astrocytes) in the ACC. A trend toward an increased SST to PV expression ratio was observed in KA-exposed slices, although no significant effects of KA or PCP on glial or PNN expression were detected. These findings suggest that targeting mGlu2 and σ1 receptors may mitigate PCP-induced network disruptions in the ACC, offering potential therapeutic strategies for addressing cognitive dysfunction in schizophrenia.