Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Abstract

A de novo mutation in the KCND2 gene, which encodes the Kv4.2 K + channel, was identified in twin boys with intractable, infantonset epilepsy and autism. Kv4.2 channels undergo closed-state inactivation (CSI), a mechanism by which channels inactivate without opening during subthreshold depolarizations. CSI dynamically modulates neuronal excitability and action potential back propagation in response to excitatory synaptic input, controlling Ca 2+ influx into dendrites and regulating spike timing-dependent plasticity. Here, we show that the V404M mutation specifically affects the mechanism of CSI, enhancing the inactivation of channels that have not opened while dramatically impairing the inactivation of channels that have opened. The mutation gives rise to these opposing effects by increasing the stability of the inactivated state and in parallel, profoundly slowing the closure of open channels, which according to our data, is required for CSI. The larger volume of methionine compared with valine is a major factor underlying altered inactivation gating. Our results suggest that V404M increases the strength of the physical interaction between the pore gate and the voltage sensor regardless of whether the gate is open or closed. Furthermore, in contrast to previous proposals, our data strongly suggest that physical coupling between the voltage sensor and the pore gate is maintained in the inactivated state. The state-dependent effects of V404M on CSI are expected to disturb the regulation of neuronal excitability and the induction of spike timing-dependent plasticity.Our results strongly support a role for altered CSI gating in the etiology of epilepsy and autism in the affected twins.ecently, a de novo mutation in the KCND2 gene was identified by exome sequencing in monozygotic twin boys with intractable seizures starting in infancy, autism, and intellectual disability (1). KCND2 encodes the Kv4.2 voltage-gated K + channel. Kv4.2 and other members of the Kv4 family serve as the pore-forming subunits in inactivating, somatodendritic A-type K + (I SA ) channels, which are widely expressed in the brain (2-8). Kv4.2 is the sole pore-forming subunit in I SA channels found in pyramidal cells in the CA1 region of the hippocampus (6, 7). The hallmark property of I SA channels is the ability to inactivate without opening during subthreshold excitatory postsynaptic potentials (5,8,9). This occurs through the mechanism of closedstate inactivation (CSI) (5, 10). CSI determines the steady-state availability of I SA channels and thereby controls resting excitability and firing frequency (5,8,9). In addition, CSI temporarily increases excitability in response to excitatory synaptic input, boosting the back propagation of action potentials and Ca 2+ influx into dendrites (7,(11)(12)(13)(14)(15)(16)(17). As a result, CSI is a key component in mechanisms of spike timing-dependent synaptic plasticity (13, 17). We previously reported that V404M, the Kv4.2 mutation associated with epilepsy and autism, impairs CSI, but the underlying m...

IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism

“…Interestingly, many of the genes that were impacted by IGF-1 treatment in controls have been associated with ASD and other neurodevelopmental disorders which may indicate that caution should be used when studying the effects of IGF-1 on neurotypical controls. For example, GPS2 is a component of the nuclear receptor co-receptor (NCOR-SMRT) complex which interacts with methyl CpG binding protein 2 (MeCP2) to regulate silencing and has been implicated in the etiology of Rett syndrome [30], HSP90AB1 is elevated in ASD patients [31], and the potassium channel protein, KCND2 (Kv4.2), has been associated with a case of twins that were comorbid for ASD and seizures [32,33].…”

Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current

“…Complexes as a Mechanism Underlying Epilepsy Kv4 channels underlie the main somatodendritic A-type Kv currents in most hippocampal pyramidal neurons and play a critical role in regulating suprathreshold dendritic signals such as dendritic action potential backpropagation, furthering dendritic Ca 2+ influx and excitability (Chen et al, 2006). The relevance of Kv4.2 to epilepsy is supported by the identifications of a C-terminal truncation mutation of Kv4.2 in patients with TLE (Singh et al, 2006) and a de novo mutation in KCND2 gene that enhances closed-state inactivation (CSI) of Kv4.2, causing epilepsy onset (Lin et al, 2018), and the observations from Kv4.2 knockout mice showing increased susceptibility to seizures induced by KA (Barnwell et al, 2009). Studies in animal epilepsy models also demonstrate a reduction of Kv4.2 mRNA in the dentate granule cells of the hippocampus (Tsaur et al, 1992); an activity-dependent reduction of Kv4 A-type currents (Bernard et al, 2004), which might result from increased Kv4.2 internalization (Kim et al, 2007), and microRNA miR-324-5p-mediated downregulation of Kv4.2 (Gross et al, 2016); and selective increase of Kv4.2-mediated I A by a triterpene saponin saikosaponin A inhibiting chronic TLE (Hong et al, 2018).…”

Increased hippocampal excitability in miR-324-null mice

“…miR-324-5p has also been investigated in relation to epilepsy; in a murine model of epilepsy, whereby wild-type (WT) mice were injected with pilocarpine in order to evoke seizure activity, the use of a miR-324-5p antagomir was found to reduce the incidence of epileptic events 30 , purportedly by downregulating the expression of Kcnd2 , a gene encoding the potassium channel protein Kv4.2 29 , 30 . Deletion or mutation of Kcnd2 has been shown to severely impair A-type K + currents 35 – 37 . A detailed investigation into the cause of the association between miR-324 and epilepsy has however not yet been reported.…”