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

Neuron. 2016 Apr 20;90(2):292-307. doi: 10.1016/j.neuron.2016.03.001. Epub 2016 Mar 31.

Abstract

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 Ca(2+) influx through CaV1 channels triggers CaM nuclear translocation via local Ca(2+) 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 Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Auditory Cortex / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Caveolin 1 / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Interneurons / metabolism*
  • Interneurons / physiology
  • Isoenzymes / metabolism
  • Mice
  • Neurons / metabolism
  • Neurons / physiology*
  • Parvalbumins / metabolism*
  • Phosphorylation
  • Rats
  • Signal Transduction*
  • Transcription, Genetic / physiology*

Substances

  • Cav1 protein, mouse
  • Caveolin 1
  • Cyclic AMP Response Element-Binding Protein
  • Isoenzymes
  • Parvalbumins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium