Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons

• Published in: Neuron (Cambridge, Mass.) Vol. 90; no. 2; pp. 292 - 307
• Main Authors: Cohen, Samuel M., Ma, Huan, Kuchibhotla, Kishore V., Watson, Brendon O., Buzsáki, György, Froemke, Robert C., Tsien, Richard W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2016; Elsevier Limited
• Subjects: Acoustic Stimulation; Animals; Auditory Cortex - metabolism; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Caveolin 1 - physiology; Cyclic AMP Response Element-Binding Protein - metabolism; Experiments; Gene expression; Immunoglobulins; Interneurons - metabolism; Interneurons - physiology; Isoenzymes - metabolism; Kinases; Mice; Neurons; Neurons - metabolism; Neurons - physiology; Parvalbumins - metabolism; Phosphorylation; Rats; Signal Transduction; Statistical analysis; Transcription, Genetic - physiology
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2016.03.001

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 CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. 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. •Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression.