Dose‐ and Age‐Dependent Effects of Prenatal Ethanol Exposure on Hippocampal Metabotropic‐Glutamate Receptor‐Stimulated Phosphoinositide Hydrolysis

Abstract

Prenatal ethanol exposure reduces the density of the N-methyl-D-aspartate (NMDA) receptor agonist binding sites and decreases the capacity to elicit long-term potentiation (LTP) in hippocampal formation of 45-day-old rat offspring. We hypothesized that prenatal ethanol exposure would reduce metabotropic-glutamate receptor (mGluR)-activated phosphoinositide hydrolysis also. Sprague-Dawley rat dams were fed a liquid diet containing either 3.35% (v/v) ethanol or 5.0% ethanol throughout gestation. Control groups were pair-fed either isocalorically matched 0% ethanol liquid diets or lab chow ad libitum. (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) stimulated inositol-1-phosphate (IP1) accumulation via activation of the mGluR in offspring whose mothers consumed the 3.35% ethanol liquid diet was not different compared with the control groups. Furthermore, trans-ACPD stimulated IP1 accumulation in 10- to 13-day-old offspring of the 5.0% ethanol diet group was not different compared with the control groups. However, trans-ACPD stimulated IP1 accumulation was reduced significantly in 56- to 82-day-old offspring of dams fed the 5.0% ethanol liquid diet compared with the control groups. In contrast, bethanechol stimulated IP1 accumulation, mediated via activation of muscarinic cholinergic receptors, was not affected by maternal consumption of either ethanol liquid diet. These results suggest both dose- and age-dependent effects of prenatal ethanol exposure on hippocampal responsiveness to trans-ACPD-activated phosphoinositide hydrolysis. Furthermore, the ability of the 3.35% ethanol diet to alter hippocampal NMDA receptors without altering the mGluR response suggests a differential sensitivity to the effects of ethanol exposure in utero among hippocampal glutamate receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring

“…However, it is known that activation of postsynaptic processes dependent on stimulation of glutamate receptors, including NMDA and metabotropic subtypes, is essential for the induction of LTP (Collingridge et al, 1983;Morris et al, 1986;Otani and Ben-Ari, 1991;Kelso et al, 1992). In this regard, earlier observations that prenatal ethanol exposure decreases the affinity of hippocampal NMDA receptors for binding glutamate (Savage et al, 1991) and decreases hippocampal mGluR (ACPD)-stimulated IP 1 accumulation (Queen et al, 1993) are important. Each one of these demonstrated effects of prenatal ethanol exposure occurs at a locus that could significantly reduce long-term synaptic enhancement in the dentate gyrus and at other hippocampal connections.…”

“…Despite their normal appearance, neurochemical observations in these rats reveal changes in at least four subtypes of amino acid receptors and several cell signaling systems in the hippocampus that may be responsible for some functional abnormalities, and at least some of these changes are at loci critical for normal LTP. Prenatal ethanol exposure decreases the affinity of hippocampal N-methyl-D-aspartate (NMDA) receptors for binding glutamate (Farr et al, 1988a;Savage et al, 1991), decreases hippocampal kainate receptor number (Farr et al, 1988b), decreases hippocampal metabotropic glutamate (mGluR) receptor-stimulated phosphoinositol (IP 1 ) accumulation (Queen et al, 1993), and alters the modulatory influences of benzodiazepines and neurosteroids on GABA A receptor function (Allan et al, unpublished observations). These effects on glutamatergic receptors and GABA receptor modulation all could affect hippocampal synaptic plasticity and LTP in particular.…”

Modulation of hippocampal long-term potentiation by slow increases in ethanol concentration

“…Whether acute ethanol tolerance alters mGluR function is unclear, although prenatal ethanol exposure decreases mGluR5 expression in the dentate gyrus (Galindo et al, 2004) and reduces mGluR-activated phosphoinositide (PI) hydrolysis (Queen et al, 1993). PI hydrolysis is involved in the formation of inositol triphosphate (IP 3 ), an intracellular messenger that activates IP 3 receptors on calcium stores, leading to calcium release.…”

Glutamatergic Neurotransmission in Alcoholism

“…Prental ethanol exposure reduces metabotropic glutamate receptor-stimulated phosphoinositide hydrolysis in both neuronal [101] and glial populations [122]. The effect is developmental-specific and the molecular action is exerted through an interaction with receptor-G-protein coupling [10,132].…”