RESUMO
De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.
Assuntos
Epilepsia , Canais de Potássio Shaw , Humanos , Canais de Potássio Shaw/genética , Interneurônios , Córtex Cerebral , Epilepsia/genética , MutaçãoRESUMO
The brain's functionality is developed and maintained through synaptic plasticity. As synapses undergo plasticity, they also affect each other. The nature of such 'co-dependency' is difficult to disentangle experimentally, because multiple synapses must be monitored simultaneously. To help understand the experimentally observed phenomena, we introduce a framework that formalizes synaptic co-dependency between different connection types. The resulting model explains how inhibition can gate excitatory plasticity while neighboring excitatory-excitatory interactions determine the strength of long-term potentiation. Furthermore, we show how the interplay between excitatory and inhibitory synapses can account for the quick rise and long-term stability of a variety of synaptic weight profiles, such as orientation tuning and dendritic clustering of co-active synapses. In recurrent neuronal networks, co-dependent plasticity produces rich and stable motor cortex-like dynamics with high input sensitivity. Our results suggest an essential role for the neighborly synaptic interaction during learning, connecting micro-level physiology with network-wide phenomena.