Dataset Information

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

ABSTRACT: 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.

SUBMITTER: Li B

PROVIDER: S-EPMC9310388 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

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

Cell 20200602 7

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 ...[more]

PMID: 32492405

Similar Datasets

Project description:Across the mammalian nervous system, neurotrophins control synaptic plasticity, neuromodulation, and neuronal growth. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is known to promote structural and functional synaptic plasticity in the hippocampus, the cerebral cortex, and many other brain areas. In recent years, a wealth of data has been accumulated revealing the paramount importance of BDNF for neuronal function. BDNF signaling gives rise to multiple complex signaling pathways that mediate neuronal survival and differentiation during development, and formation of new memories. These different roles of BDNF for neuronal function have essential consequences if BDNF signaling in the brain is reduced. Thus, BDNF knock-out mice or mice that are deficient in BDNF receptor signaling via TrkB and p75 receptors show deficits in neuronal development, synaptic plasticity, and memory formation. Accordingly, BDNF signaling dysfunctions are associated with many neurological and neurodegenerative conditions including Alzheimer's and Huntington's disease. However, despite the widespread implications of BDNF-dependent signaling in synaptic plasticity in healthy and pathological conditions, the interplay of the involved different biochemical pathways at the synaptic level remained mostly unknown. In this paper, we investigated the role of BDNF/TrkB signaling in spike-timing dependent plasticity (STDP) in rodent hippocampus CA1 pyramidal cells, by implementing the first subcellular model of BDNF regulated, spike timing-dependent long-term potentiation (t-LTP). The model is based on previously published experimental findings on STDP and accounts for the observed magnitude, time course, stimulation pattern and BDNF-dependence of t-LTP. It allows interpreting the main experimental findings concerning specific biomolecular processes, and it can be expanded to take into account more detailed biochemical reactions. The results point out a few predictions on how to enhance LTP induction in such a way to rescue or improve cognitive functions under pathological conditions.

Dataset Information

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Publications

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets