Prolonged exposure to NMDAR antagonist induces cell-type specific changes of glutamatergic receptors in rat prefrontal cortex

Abstract

N-methyl-D-aspartic acid (NMDA) receptors are critical for both normal brain functions and the pathogenesis of schizophrenia. We investigated the functional changes of glutamatergic receptors in the pyramidal cells and fast-spiking (FS) interneurons in the adolescent rat prefrontal cortex in MK-801 model of schizophrenia. We found that although both pyramidal cells and FS interneurons were affected by in vivo subchronic blockade of NMDA receptors, MK-801 induced distinct changes in αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors in the FS interneurons compared with pyramidal cells. Specifically, the amplitude, but not the frequency, of AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) in FS interneurons was significantly decreased whereas both the frequency and amplitude in pyramidal neurons were increased. In addition, MK-801-induced new presynaptic NMDA receptors were detected in the glutamatergic terminals targeting pyramidal neurons but not FS interneurons. MK-801 also induced distinct alterations in FS interneurons but not in pyramidal neurons, including significantly decreased rectification index and increased calcium permeability. These data suggest a distinct cell-type specific and homeostatic synaptic scaling and redistribution of AMPA and NMDA receptors in response to the subchronic blockade of NMDA receptors and thus provide a direct mechanistic explanation for the NMDA hypofunction hypothesis that have long been proposed for the schizophrenia pathophysiology.

Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

“…This may take the form of a lack of recovery of receptor numbers, but could also derive from changes in NMDA receptor subunit constellations and /or distributions as a result of MK801 application. Evidence of the latter, following subchronic MK801-treatment has been reported (Wang and Gao, 2012). NMDA receptor hypofunction is believed to contribute to schizophrenia-spectrum disorders including psychosis (Coyle et al, 2003; Vrajová et al, 2010).…”

Periadolescent Exposure to the NMDA Receptor Antagonist MK-801 Impairs the Functional Maturation of Local GABAergic Circuits in the Adult Prefrontal Cortex

“…The neurobiology underlying such an effect appears to be mediated by an enhancement of PFC metabolic activity, as revealed by neuroimaging studies conducted in healthy volunteers exhibiting psychotic symptoms and cognitive abnormalities in response to sub-anesthetic doses of ketamine (Breier et al, 1997; Holcomb et al, 2001; Holcomb et al, 2005). Studies conducted in animal models further indicate that the augmented PFC output induced by acute psychotomimetic doses of NMDA antagonists (Moghaddam and Adams, 1998; Jackson et al, 2004; Labonte et al, 2009; Kiss et al, 2011; Wood et al, 2012) can be triggered by a disinhibitory mechanism mediated by a functional impairment of GABAergic interneuronal activity in cortical circuits (Grunze et al, 1996; Jackson et al, 2004; Zhang et al, 2008; Wang and Gao, 2012). Our present study expands upon these findings by showing that an enduring state of prefrontal disinhibition can emerge if repeated MK-801 exposure occurs during adolescence.…”

Losing your inhibition: Linking cortical GABAergic interneurons to schizophrenia

“…Thus, it is unclear how NMDAR hypofunction in PV + cINs would manifest into a later-developing disease like SCZ, when NMDAR-mediated currents are already low in these neurons at this stage of development. A recent study may explain this conflict with the finding that prolonged exposure of MK801 leads to a reduction in the amplitude of AMPAR-mediated synaptic currents in FS PV + cINs but an increase in the amplitude of AMPAR-mediated synaptic currents in pyramidal cells (Wang and Gao, 2012). Hence, early NMDAR hypofunction may lead to a reduction in AMPA-mediated synaptic currents specifically in FS cINs, possibly through an LTD-like mechanism, although an NMDAR-dependent LTD is yet to be shown at these synapses.…”

“…Furthermore, the addition of new presynaptic NMDARs is observed in axon terminals targeting pyramidal cells but not FS PV + cINs (Wang and Gao, 2012). Since presynaptic NMDARs can facilitate glutamate release (Corlew et al, 2008), this mechanism likely explains the observation of increased frequency of AMPAR-mediated synaptic currents of pyramidal cells and not that of FS PV + cINs.…”