Journal
NEURON
Volume 90, Issue 2, Pages 292-307Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2016.03.001
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Funding
- National Institute of General Medical Sciences (NIGMS) [GM058234]
- National Institute of Neurological Disorders and Stroke (NINDS) [NS24067]
- National Institute of Mental Health (NIMH) [MH071739]
- Simons Foundation
- Mathers Foundation
- Burnett Family Foundation
- Medical Scientist Research Service Award [T32GM007308]
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Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through Ca(V)1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by gamma CaMKI, not gamma CaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.
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