Moderate Prenatal Alcohol Exposure Enhances GluN2B Containing NMDA Receptor Binding and Ifenprodil Sensitivity in Rat Agranular Insular Cortex

Abstract

Prenatal exposure to alcohol affects the expression and function of glutamatergic neurotransmitter receptors in diverse brain regions. The present study was undertaken to fill a current gap in knowledge regarding the regional specificity of ethanol-related alterations in glutamatergic receptors in the frontal cortex. We quantified subregional expression and function of glutamatergic neurotransmitter receptors (AMPARs, NMDARs, GluN2B-containing NMDARs, mGluR1s, and mGluR5s) by radioligand binding in the agranular insular cortex (AID), lateral orbital area (LO), prelimbic cortex (PrL) and primary motor cortex (M1) of adult rats exposed to moderate levels of ethanol during prenatal development. Increased expression of GluN2B-containing NMDARs was observed in AID of ethanol-exposed rats compared to modest reductions in other regions. We subsequently performed slice electrophysiology measurements in a whole-cell patch-clamp preparation to quantify the sensitivity of evoked NMDAR-mediated excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of AID to the GluN2B negative allosteric modulator ifenprodil. Consistent with increased GluN2B expression, ifenprodil caused a greater reduction in NMDAR-mediated EPSCs from prenatal alcohol-exposed rats than saccharin-exposed control animals. No alterations in AMPAR-mediated EPSCs or the ratio of AMPARs/NMDARs were observed. Together, these data indicate that moderate prenatal alcohol exposure has a significant and lasting impact on GluN2B-containing receptors in AID, which could help to explain ethanol-related alterations in learning and behaviors that depend on this region.

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

“…We have observed a regionally-specific increase in GluN2B-containing NMDA receptor binding based on radiohistochemical studies in rats exposed to ethanol during gestation [53]. Further, in the same study, we demonstrated that evoked NMDA currents from layer II/III pyramidal neurons in AIC in PAE rats are more sensitive to the effects of ifenprodil, a negative allosteric modulator of GluN2B containing NMDA receptors, than saccharin controls.…”

Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

“…Other highly disturbed is the glutamatergic system, mainly the regionally specific glutamate receptor expression (Bird et al, 2015). Particularly, NMDA receptor subunits are affected.…”

“…Also, a functional NMDA-NR1 receptors are necessary for the neurotoxic and teratogenic effects of PAE (Deng and Elberger, 2003). Additionally, synaptic NR2B-containing NMDA receptor concentrations are reduced in PAE animals (Samudio-Ruiz et al, 2010), specifically in the agranular insular cortex (Bird et al, 2015). Taken together, these evidences could help to explain EtOH-related alterations in learning and behaviors that depend on cerebral cortex.…”

“…PAE reduces the concentrations of some catecholamines, indolamine, and amino acid neurotransmitters in E13 fetal brains (Sari et al, 2010). In also affects the GABAergic system (Volgin, 2008; Zhou et al, 2010; Wang et al, 2013), serotonin (Sliwowska et al, 2014), and opioid receptors (Nizhnikov et al, 2014) in a number of brain regions (Bird et al, 2015 and references therein). Thus, it would be of interest to study these systems under the ADHD condition.…”

Effects of sex and housing on social, spatial, and motor behavior in adult rats exposed to moderate levels of alcohol during prenatal development

“…In a recent study [20] we replicated the effect of moderate PAE on male social behavior and observed impaired motor behaviors (tongue protrusion [78, 79]), and decreased behavioral flexibility as measured by increases in perseverative errors in the Morris water task. This collection of deficits was of particular interest based on commonalities in the ventrolateral frontocortical circuitry required for these behaviors and reports of alterations in ventrolateral frontal cortex function following moderate PAE [6, 19, 22]. …”