A potential role for nerve growth factor in regulating the maturation of inhibitory neurotransmission.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Lagostena et al. Interneurons mediate inhibition in the CNS by releasing GABA, which hyperpolarizes postsynaptic neurons by promoting chloride entry through GABA A receptors. Low levels of intracellular chloride ([Cl Ϫ ] i) in postsynaptic neurons, maintained by the chloride exporter KCC2, are required for the hyperpolarizing activity of GABA (Rivera et al., 1999). During early postnatal development, KCC2 expression is low, while expression of the chloride importer NKCC1 is elevated. As a result, [Cl Ϫ ] i is increased, making the reversal potential of GABA-mediated currents (E GABA) depolarized relative to the resting membrane potential in young neu-rons. Consequently, GABA activates chloride efflux through GABA A receptors and depolarizes postsynaptic neurons (Plot-kin et al., 1997; Rivera et al., 1999). While the relative contributions of NKCC1 and KCC2 to chloride homeostasis are well understood, the molecular mechanisms responsible for regulating their expression during development remain unclear. Evidence from the chick ciliary gan-glion has implicated nicotinic cholinergic signaling in the regulation of developmental changes in KCC2 and NKCC1 expression. Calcium influx through nicotinic acetylcho-line receptors (nAChRs) activates the transcription factor CREB, which is thought to result in upregulation of KCC2 and down-regulation of NKCC1 as early postnatal development progresses (Liu et al., 2006). Recent work from Lagostena et al. (2010), using mice with deficient nerve growth factor (NGF) signaling, highlights NGF as another potentially important factor in regulation of chloride homeostasis. In this study, the consequences of NGF loss were examined using AD11 mice, which express antibodies directed against NGF. These mice exhibit impaired NGF signaling, neu-rodegeneration, and cognitive dysfunction (Capsoni et al., 2000). Lagostena et al. (2010) examined 6-month-old AD11 mice, an age at which NGF deprivation had begun to induce neurodegeneration and other defects. In AD11 mice, Lagostena et al. (2010) found that GABA depolarized, rather than hyperpolarized, adult hippocampal neu-rons. Consistent with the prediction that hippocampal neurons in these mice exhibit high [Cl Ϫ ] i , the authors report that KCC2 mRNA and protein were both reduced in the AD11 mouse hippocampus. The authors propose that loss of NGF signaling turns on the same genetic …