Early postnatal GABAB antagonist treatment normalizes inhibitory/excitatory balance in neonatal Ts65Dn mice, a genetic model of down syndrome

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Joshua Jin, James Doan, Cassandra Fernandez, Samuel Nguyen, Cole Spencer, Alexander M. Kleschevnikov
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引用次数: 0

Abstract

Brain abnormalities in Down syndrome (DS) most rapidly accumulate during the third trimester, a critical period for the formation of neural circuits in the hippocampus and neocortex. In mice, this stage roughly corresponds to the first 2.5 weeks after birth. We hypothesized that enhanced Girk2 channel signaling during this critical period profoundly contributes to the formation of faulty neural circuits in mouse genetic models of DS, with a key feature being an imbalance of excitatory and inhibitory neurotransmission favoring inhibition. Major predictions of this hypothesis were tested. We observed that hippocampal Girk2 levels are enhanced, GABAB/Girk2 signaling efficiency is increased, and intrinsic neuronal excitability of dentate gyrus (DG) granule cells is reduced in neonatal Ts65Dn mice. Given this, we tested if suppressing the enhanced GABAB/Girk2 signaling in the early postnatal period would affect the inhibitory/excitatory (I/E) balance in Ts65Dn mice. Remarkably, GABAB antagonist treatment from postnatal day 2 (P2) to P17 normalized the exaggerated IPSC/EPSC ratio in DG granule cells in Ts65Dn mice. Our findings show that GABAB/Girk2 signaling is increased in neonatal Ts65Dn mice, and that pharmacological suppression of GABAB receptors during the early postnatal period normalizes the I/E balance. These results suggest that early intervention targeting GABAB/Girk2 signaling could be a promising therapeutic approach to mitigate cognitive impairment in DS.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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