Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
['Li|Boxing|B|', 'Suutari|Benjamin S|BS|', 'Sun|Simón(e) D.|SD|', 'Luo|Zhengyi|Z|', 'Wei|Chuanchuan|C|', 'Chenouard|Nicolas|N|', 'Mandelberg|Nataniel J|NJ|', 'Zhang|Guoan|G|', 'Wamsley|Brie|B|', 'Tian|Guoling|G|', 'Sanchez|Sandrine|S|', 'You|Sikun|S|', 'Huang|Lianyan|L|', 'Neubert|Thomas A|TA|', 'Fishell|Gordon|G|', 'Tsien|Richard W|RW|']
D000200:Action Potentials D017398:Alternative Splicing D000818:Animals D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 D017871:Calcium-Calmodulin-Dependent Protein Kinases D005260:Female D057809:HEK293 Cells D006706:Homeostasis D006801:Humans D051036:Large-Conductance Calcium-Activated Potassium Channels D017774:Long-Term Potentiation D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009419:Nerve Tissue Proteins D000090682:Neuro-Oncological Ventral Antigen D009473:Neuronal Plasticity D009474:Neurons D016601:RNA-Binding Proteins D051381:Rats D017207:Rats, Sprague-Dawley D015398:Signal Transduction D013569:Synapses D009435:Synaptic Transmission
homeostasis Alternative splicing chronic inactivity action potential duration BK channel Nova-2 CaM kinase synaptic activity