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Maturation and Pharmacological Properties of Postsynaptic GABAA Receptors
Author(s) -
Wang Haiying,
Griffith William H.,
McDermott Angelika N.,
Murchison David,
Frye Gerald D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1127.12
Subject(s) - zolpidem , long term potentiation , gabaa receptor , postsynaptic potential , medicine , endocrinology , chemistry , pharmacology , receptor , insomnia
Medial Septum/Diagonal Band (MS/DB) neurons display age‐dependent acceleration of GABA miniature postsynaptic current (mPSC) frequency, amplitude and decay rate in brain slices over postnatal day (PD) 4–16 (DuBois and Frye SfN Abst, 34: 913.11, 2004). ‘Binge‐like’ alcohol exposure on PD 4–9 equivalent to 3 rd trimester of human pregnancy blunted this maturation, possibly by disrupting clustering of α1 containing GABA A Rs at synapses (Wang and Frye SfN Abst, 34: 570, 2006). In the present study, potentiation by zopidem (0.3–100 μM), a positive allosteric modulator with preferred selectivity for α1 subunit containing GABA A Rs, was examined in MS/DB neurons in brain slices from PD 4–9 Naïve pup and older rats of 3–4, 17 or 24 months. Zolpidem potentiation after binge‐like ethanol on PD 4–9 (5.25g/kg/day) was investigated during PD 11–16 and PD 80–85. GABA A R–mediated mPSCs were recorded in presence of zolpidem and amplitude, frequency and decay kinetics were analyzed. Zolpidem (0.3–100 μM) showed an age‐dependent potentiation of mPSC decay during PD 4–16 and plateaued in adulthood. The fast decay potentiation by zolpidem in adult and old rats resembled that of PD 4–9 naïve pups; Potentiation of the slow decay resembled that of PD 11–16 control rats. Binge ethanol exposure on PD 4–9 blunted zolpidem potentiation on PD 11–16, which persists through PD 80–85. No gender differences in baseline or zolpidem sensitivity on PD 11–16 were observed after binge ethanol treatment on PD 4–9. These results suggest binge ethanol exposure in developing MS/DB neurons appears to cause long‐term distortion of pharmacological sensitivity of postsynaptic GABA A Rs, which could contribute to cognitive deficits identified in fetal alcohol spectrum disorders. Supported in part by NIH R56AA12386 (GDF), RO1 AG007805 (WHG), T32 MH65728 (ANM)