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J Neurophysiol. 2018 Nov 1;120(5):2358-2367. doi: 10.1152/jn.00287.2018. Epub 2018 Aug 15.

Pyramidal cell activity levels affect the polarity of activity-induced gene transcription changes in interneurons.

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Institute of Neuroscience, Medical School , Newcastle University, Newcastle upon Tyne , United Kingdom.
Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University , New York, New York.

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Changes in gene expression are an important mechanism by which activity levels are regulated in the nervous system. It is not known, however, how network activity influences gene expression in interneurons; since they themselves provide negative feedback in the form of synaptic inhibition, there exists a potential conflict between their cellular homeostatic tendencies and those of the network. We present a means of examining this issue, utilizing simple in vitro models showing different patterns of intense network activity. We found that the degree of concurrent pyramidal activation changed the polarity of the induced gene transcription. When pyramidal cells were quiescent, interneuronal activation led to an upregulation of glutamate decarboxylase 1 ( GAD1) and parvalbumin ( Pvalb) gene transcriptions, mediated by activation of the Ras/extracellular signal-related kinase mitogen-activated protein kinase (Ras/ERK MAPK) pathway. In contrast, coactivation of pyramidal cells led to an ionotropic glutamate receptor N-methyl-d-aspartate 2B-dependent decrease in transcription. Our results demonstrate a hitherto unrecognized complexity in how activity-dependent gene expression changes are manifest in cortical networks. NEW & NOTEWORTHY We demonstrate a novel feedback mechanism in cortical networks, by which glutamatergic drive, mediated through the Ras/ERK MAPK pathway, regulates gene transcription in interneurons. Using a unique feature of certain in vitro epilepsy models, we show that without this glutamatergic feedback, intense activation of interneurons causes parvalbumin and glutamate decarboxylase 1 mRNA expression to increase. If, on the other hand, pyramidal cells are coactivated with interneurons, this leads to a downregulation of these genes.


MAPK pathway; epilepsy; epileptogenesis; homeostasis; parvalbumin

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