Abstracts

Rationale: Striatal enriched protein phosphatase (STEP) is a brain specific tyrosine phosphatase that regulates Hebbian and homeostatic plasticity by negatively regulating NMDA- and AMPA- subtype glutamate receptors at excitatory synapses. Previously, our lab reported that prolonged manipulation of hippocampal network activity changes STEP61 expression and activity, resulting in modulating synaptic weight against altered network activity in a homeostatic manner. Despite a well-established role of STEP61 in regulating synaptic activity, it is unclear whether STEP regulates the function of other ion channels that contribute to intrinsic excitability of hippocampal neurons. Methods: Transgenic miceElectrophysiologyWestern blotHippocampal slice Primary Hippocampal cultureCHO cell culture Results: Our findings show that STEP knock-out (KO) mice display prolonged latency to convulsion, reduced cumulative seizure scores, and decreased death rate following I.P injection of chemoconvulsant kainic acid (30 mg/kg), suggesting that STEP KO mice are resistant to kainic acid-induced status epilepticus (SE). Genetic ablation of STEP leads to elevated voltage sag, rebound potential, hyperpolarization-induced inward currents (Ih) and tail currents  in hippocampal neurons located at CA2 regions where STEP61 is highly enriched in wild-type (WT) mice. Consistently, acute inhibition of endogenous STEP activity in cultured hippocampal neurons enhances Ih and voltage sag. Lastly, transient expression of wild-type STEP61 and HCN2 in CHOhm1 cells reduces total protein and current expression of HCN2 channels.  Conclusions: STEP is a negative modulator for the function of HCN channels, contributing to hippocampal excitability and seizure propensity.  Funding: R01 NS083402 from National Institute of Health, National Institute of Neurological Disorders and StrokeR01 NS097610 from National Institute of Health, National Institute of Neurological Disorders and Stroke (2016-2021)