Abstract
Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC) and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg), a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV)-, calbindin (CB)- and calretinin (CR)-positive neurons in mPFC was analyzed at either 24 h or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.
Highlights
It is widely accepted that schizophrenia is a neurodevelopmental disorder (Fatemi and Folsom, 2009)
We examined how repeated blockade of NMDA receptors by MK-801 during adolescence would affect PFCmediated cognitive functions and GABAergic interneurons in rat medial prefrontal cortex (mPFC)
We found that rats receiving MK-801 treatment exhibited delayed reversal learning in the water maze without affecting acquisition
Summary
It is widely accepted that schizophrenia is a neurodevelopmental disorder (Fatemi and Folsom, 2009). Deficits in the inhibitory gamma-aminobutyric-acid (GABA)ergic interneurons have been consistently found in the prefrontal cortex (PFC) of schizophrenic patients (Reynolds et al, 2004). These deficits are thought to contribute to the disturbances of PFC-dependent cognitive functions in schizophrenia, since GABAergic transmission is critical for normal cognitive functions via producing synchronized network oscillations (Uhlhaas et al, 2006; Gonzalez-Burgos et al, 2011). The maturation of GABAergic interneurons involves the N-methyl-D-aspartate (NMDA) receptors (Thomases et al, 2013), which are highly relevant to the pathophysiology of schizophrenia, considering that blocking the NMDA receptors using its antagonists, such as phencyclidine (PCP), MK-801 or ketamine, constitutes one of the most widely used animal models for schizophrenia (Jentsch and Roth, 1999). Investigating how repeated blockade of NMDA receptors during adolescence would affect GABAergic interneurons in the PFC would provide insight to the mechanisms underlying the onset of the disease
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