Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

Abstract

N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.

Specific Roles of NMDA Receptor Subunits in Mental Disorders

“…Prenatal treatment with PCP causes cognitive impairment of memory, PCP sensitization, and deficits of sensorimotor gating [152, 153]. These behavioral deficits may be caused by impairments in the neuronal progenitor proliferations and decreased densities of glutamatergic neurons in the prefrontal cortex following prenatal PCP treatment [154]. Prenatally PCP-administered mice display behavioral deficits in cognitive memory and sensorimotor gating until adulthood, and they are used as an experimental model of schizophrenia.…”

Autocrine glutamatergic transmission for the regulation of embryonal carcinoma stem cells

“…Activation of the receptor increases neurogenesis in dentate gyrus and antagonism of the receptor blocks the neuronal progenitor proliferation in the ventricular and the subventricular zone [30–33]. This effect is partly attributed to the mechanisms such as receptor activation-induced Rb phosphorylation, calcium/calmodulin/CREB stimulation, and mitogenic factor release [30, 32].…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Early oligodendrocyte progenitor cell markers were decreased in rat brains prenatally exposed to PCP (10 mg/kg), suggesting that surviving cells are arrested at an immature stage, which might have implications for the role of glutamate and glutamate receptors in white matter abnormalities in neurodevelopmental disorders (Lindahl et al, 2008). These findings were strengthened by another recent report on prenatally PCP-treated mice, demonstrating aberrant gene expression (Notch2 and Ntn1) and consequential decrease in the density of glutamatergic neurons in the PFC, deficits in cognitive memory, and sensorimotor gating at adulthood (Toriumi et al, 2012).…”