The effects of 'binge' ethanol exposure on the development of GABA (subscript A) receptors in rat brain : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2004]
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| Abstract: | ABSTRACTS: Early postnatal 'binge' ethanol exposure, modeling human third trimester fetal alcohol syndrome-induced brain damage, blunts the developmental up-regulation of whole cell gamma-aminobutyric acid type A receptor (GABAAR) function on acutely dissociated septal neurons (Hsiao et al., 1998; 2001). Here, experiments were performed to further characterize the action of 'binge' ethanol exposure using cultured septal neurons. GABAAR-mediated miniature postsynaptic currents (mPSCs) demonstrated an age-dependent up-regulation in frequency and decay kinetics suggesting that these neurons experience synapse formation and maturation in vitro. In this system, 'binge' ethanol exposure (6-11 days in vitro (DIV)) blunted mPSC amplitude and frequency, and slowed decay kinetics of mPSC recorded DIV 13-18. Acute ethanol application to untreated septal neurons decreased mPSC amplitude and frequency without changing decay kinetics while sustained inhibition of GABAARs with 100 uM picrotoxin (DIV 6-11) decreased mPSC amplitude and frequency and slowed decay kinetics similar to 'binge' ethanol. This suggest that ethanol and picrotoxin delay mPSC maturation by interfering with GABA signaling during synapse formation in septal neurons. Age-dependent increases in potentiation of mPSC decay kinetics to the GABAAR α1 selective compound, solpidem, were assocated with increased expression of GABAAR α1 protein. 'Binge' ethanol decreased zolpidem potentiation but did not decrease GABAAR α1 expression as might be expected for decreases in zolpidem potentiation. Maturing neurons also demonstrated reduced zinc (Zn²⁺) inhibition, but this developmental sensitivity was not disrupted by 'binge' ethanol. In contrast, 'binge' ethanol enhanced 3α-hydroxy-dihydroxy-5α-pregnan-20-one (3α-OH-DHP) potentiation of GABAergic mPSC decay. These differences in the impact of 'binge' ethanol exposure of Allosteric modulation of GABAAR mPSCs suggest that ethanol may disrupt synpatic maturation by several distinct mechanisms Medial septum/diagonal band (MS/DB) neurons in acutely cut brain slices exhibited a developmental up-regulation of GABAAR mPSC frequency and decay kinetics between the first and second postnatal weeks. 'Binge' ethanol exposure on postnatal days (PD) 4-9 blunted mPSC amplitutde and frequency qhile slowing decay kinetics from PD 11-15. Zolpidem potentiation of GABAAR mPSCs was also decreased similar to that in septal cultures. These results suggest that development of GABAAR synpatic function in vitro is similar to that in the intact brain, and 'binge' ethanol has similar impacts on the development of GABAAR mPSCs in both preparations. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy August 2004." Approved as to style and content by: Gerald D. Frye, William H. Griffith, Brian A McCool, Mark J. Zoran, Ursula WInzer-Serhan, George C. Y. Chiou. |
| Physical Description: | xiii, 119 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 101-116). |