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Development of GABAA receptors on medial septum/diagonal band (MS/DB) neurons after postnatal ethanol exposure
S H Hsiao1, J C Mahoney, J R West
1Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
Insights
Early postnatal binge-like ethanol exposure disrupts gamma-aminobutyric acid type A receptor (GABAAR) development in rat brain regions. These disruptions may contribute to neurobehavioral deficits seen in fetal alcohol syndrome.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Gamma-aminobutyric acid type A receptors (GABAARs) are crucial for neuronal inhibition.
- GABAAR function undergoes significant developmental changes during early life.
- Postnatal exposure to ethanol can impact brain development and function.
Purpose of the Study:
- To investigate the effects of binge-like ethanol exposure during a critical postnatal period on GABAAR development.
- To determine how early ethanol exposure alters GABAAR function and modulation in specific brain regions.
Main Methods:
- Whole-cell patch-clamp recordings were performed on medial septum/diagonal band (MS/DB) neurons from rats at different developmental stages.
- Neurons were acutely isolated from control and ethanol-exposed rats.
- The effects of GABA, ethanol, and other allosteric modulators on GABA currents were measured.
Main Results:
- GABAAR function (maximal response and EC50) naturally increased with age in control rats.
- Early binge-like ethanol exposure reduced GABAAR maximal response and EC50 in juvenile rats, with recovery by young adulthood.
- Ethanol exposure altered age-dependent changes in GABAAR modulation, including reduced Zn2+ inhibition and blocked ethanol potentiation.
Conclusions:
- Early postnatal ethanol exposure disrupts the normal developmental trajectory of GABAAR function in MS/DB neurons.
- These disruptions may underlie neurobehavioral deficits associated with fetal alcohol syndrome.
- Further research is needed to elucidate the cellular mechanisms (e.g., damage, gene expression, post-translational modification) responsible for these changes.
Abstract:
The impact of 'binge-like' ethanol exposure on postnatal days (PD) 4-9 was examined on development of gamma-aminobutyric acid type A receptors (GABAAR) during the first month of life in the rat. Whole-cell patch-clamp recordings in acutely isolated medial septum/diagonal band (MS/DB) neurons were used to define effects of rapidly applied ethanol and other allosteric modulators on bicuculline-sensitive GABA currents. Three age groups were examined including 'pups' (PD 4-10), 'juveniles' (PD 11-16) and 'young adults' (PD 25-35). In untreated neurons, maximum responses to GABA and the apparent GABA EC50 increased approximately 2-fold during the first month of life. Potentiation of GABA responses by pentobarbital, midazolam, and loreclezole all increased with age, while Zn2+ inhibition declined. Initial inhibition by ethanol switched to potentiation of GABA responses during this time. In vivo, binge-like ethanol treatment (4.5 g kg-1 day-1 divided into two doses, 2 h apart on PD 4-9) reduced both the GABA maximal response and GABA EC50 measured on PD 11-16. These measures returned to control levels by PD 25-35. After binge-like postnatal ethanol exposure, age-dependent loss of Zn2+ inhibition of GABA responses was increased, while potentiating actions of in vitro ethanol were blocked. GABAAR modulation by other drugs was unaffected. These data suggest that early postnatal ethanol exposure disrupts the expected developmental pattern of GABAAR function in MS/DB neurons, an action that could contribute to neurobehavioral deficits associated with the fetal alcohol syndrome. Whether these changes are due to cellular damage, delayed gene expression or post-translational modification needs to be determined.