Increased expression of the NR2A NMDA receptor subunit in the prefrontal cortex of rats reared in isolation

Abstract

A hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Compelling evidence of altered NMDA receptor subunit expression in the schizophrenic brain has not, however, so far emerged. Rats reared in isolation exhibit several characteristics, including disturbed sensory gating, which resemble those seen in schizophrenia. To explore the possibility that NMDA receptor dysfunction may contribute to the behavioral and neurochemical consequences of rearing rats in isolation, we compared NMDA receptor subunit expression in brains of rats which were housed in isolation and which displayed a deficit in prepulse inhibition of the acoustic startle response with that of socially housed controls. An initial microarray analysis revealed a 1.26-fold increase in NR2A transcript in the prefrontal cortex, but not in the nucleus accumbens, of rats reared in isolation compared with those housed socially. In contrast, NR1, NR2B, NR2C, NR2D, NR3A, and NR3B subunit expression was unchanged in either brain area. In a second cohort of animals, in situ hybridization revealed increased NR2A mRNA expression in the medial prefrontal cortex, an observation that was substantiated by increased [(3)H]CGP39653 binding suggesting that NR2A receptor subunit protein expression was also elevated in the medial prefrontal cortex of the same animals. No changes in expression of NR1 or NR2B subunits were observed at both mRNA and protein level. Altered NR2A subunit expression in the medial prefrontal cortex of rats reared in isolation suggests that NMDA receptor dysfunction may contribute to the underlying pathophysiology of this preclinical model of aspects of schizophrenia.

Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

“…Accumulating evidence indicate that both chronic and acute damage due to NMDA-R antagonists may depend on the same type of the receptor containing the NR2A subunit. NR2A receptors were implicated in delayed behavioral deficits in several chronic animal models, such as in rats reared in isolation (30) or subjected to neonatal treatment with phencyclidine (14) or ventral hippocampal lesion (31) and now the results of this study show their preferential involvement in acute aberrant gamma activation after NMDA-R blockade, as well.…”

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

“…Specific glutamatergic involvement in this isolation-induced behavioural deficit has not previously been reported; however, it has been shown that the dopamine release associated with a conditioned emotional response may be regulated by glutamatergic inputs into the NAcc that requires prior NMDA receptor activation (Saulskaya and Marsden 1995a, b). Interestingly, a number of NMDA receptor subunit changes have been reported in isolation-reared animals (Hall et al 2002;Turnock-Jones et al 2009), including reduced NR1A expression in the NAcc, which may contribute to the deficits in fear conditioning seen herein. Although direct activation of mGlu2/3 receptors prior to conditioning did not appear to alter this behavioural response in isolation-reared rats, the effect of the drug at other phases of learning and memory such as consolidation and/or retrieval and whether any molecular changes in mGluR2/3 populations in these regions contribute to the impairment, still remains to be explored with chronic drug administration studies.…”

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

“…Previous microarray studies found altered expression of the NR2A NMDA receptor subunit and development-related genes (e.g. NURR1) in the prefrontal cortex (Turnock-Jones et al, 2009) and the dentate gyrus (Ibi et al, 2008) of isolation-reared rodents. However, this is the first study to report long-term effects of neonatal PCP (and isolation rearing) on gene expression.…”