Perinatal alcohol exposure leads to prolonged upregulation of hypothalamic GABAA receptors and increases behavioral sensitivity to gaboxadol

Abstract

Prenatal alcohol exposure (AE) is associated with lasting abnormalities of sleep and motor development, but the underlying mechanisms are unknown. We hypothesized that AE alters development of GABAergic signaling in the hypothalamic regions important for the control of sleep and motor activity. Alcohol (5.25 g/(kg day)) was administered intragastrically to male rats on postnatal days (PD) 4-9, a period of brain development equivalent to the human third trimester (AE group). Control pups were sham-intubated (S group). Motor activity was monitored on PD27 and 28. On PD29 and 30, GABA A receptor subunit mRNA levels and alpha4 and delta subunit proteins were quantified by RT-PCR and immunoblotting, respectively, in the wake- and motor activity-promoting perifornical (PF) region of the posterior hypothalamus and the sleep-promoting ventrolateral preoptic (VLPO) region of the anterior hypothalamus. Then, in 47-52-day-old rats, motor activity was quantified following administration of GABA A receptor agonist, gaboxadol (5 mg/kg s.c.). In the PF region, mRNA and protein levels for the alpha4 and delta subunits were significantly higher and beta3 and gamma2 subunit mRNAs were also increased in the AE group. In the VLPO region, only the delta subunit mRNA was increased. Spontaneous motor activity was lower and suppressed more by gaboxadol in the AE than S group, and the latency to a transient total loss of activity after gaboxadol was shorter in the AE group. Thus, perinatal AE leads to GABA A receptor overexpression in the vigilance- and motor activity-promoting hypothalamic PF region, with the neurochemical and functional outcomes lasting long beyond the period of the insult.

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Data from PAE models also show pro-inflammatory signalling and abnormal neuronal development in the hypothalamus, hippocampus, and cerebellum —brain regions known to be affected in individuals with FASD (Volgin 2008; Coleman et al 2012; Drew et al 2015; Smiley et al 2015). Drew et al administered 4.0 g·kg –1 ·day –1 alcohol by oral gavage, in pups from postnatal days 4–9, as a chronic high BAC third trimester alcohol exposure model.…”

“…Furthermore, PAE mice exhibited impaired contextual fear conditioning memory that was significantly correlated with slow-wave sleep fragmentation (Wilson et al 2016). Interestingly, mice with impairments in GABA A receptors (or their subunits) have learning and memory deficits, hyperactivity, and dysregulated sleep patterns, impairments reminiscent of mouse models of acute third trimester PAE (DeLorey et al 1998; Volgin 2008). While sleep disturbance patterns have been a relatively well-known co-morbidity of FASD, sleeping problems in children with FASD often goes undiagnosed, and can be associated with deficits in emotional, behavioral, and cognitive function.…”

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

“…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.…”

Loss of motoneurons in the ventral compartment of the rat hypoglossal nucleus following early postnatal exposure to alcohol

“…We used an established rat model of FASD in which rat pups are exposed to alcohol during the early postnatal period (Light et al, 1998; Kelly and Lawrence, 2008; Volgin, 2008) that corresponds to the third trimester of human pregnancy with the regard to the stage of brain development (Dobbing and Sands, 1979). All animal procedures followed the guidelines of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania.…”

“…The relative immaturity of the newborn rat brain due to a shift of the brain growth spurt to the extra uterine period makes an early postnatal AE in rats an attractive animal model of FASD (Light et al, 1998; Cudd, 2005; Kelly and Lawrence, 2008). The model has been extensively used for investigation of the neurotoxic impact of AE on brain neuroanatomy (Pierce et al, 1993), cognitive functions (Johnson and Goodlett, 2002; O'Leary-Moore et al, 2006; Stettner et al, 2011), motor control (McGough et al, 2009; Stettner et al, 2011), neurotransmitter receptor expression (Volgin, 2008) and sleep-wake behavior (Volgin and Kubin, 2012). …”