Increased Expression of Kv10.2 in the Hippocampus Attenuates Valproic Acid-Induced Autism-Like Behaviors in Rats

Wang, Jing; Feng, Shini; Li, Min; Yan, Jin; Tang, Yunfei; Du, Dongshu; Chen, Fuxue

doi:10.1007/s11064-019-02903-4

Cited by 16 publications

(6 citation statements)

References 40 publications

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“…Treatment with MP‐III‐022 did not manage to rescue the observed impairment. The reverse MWM demonstrated restrictive patterns of behavior, previously observed in Y/T mazes (Kumar & Sharma, 2016; Mirza & Sharma, 2019; Wang et al, 2019), which is another core symptom of ASD patients. This type of impairment was amenable to amelioration by MP0.3 in males, while MP1 only in part restored this performance in females.…”

Section: Discussionmentioning

confidence: 58%

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

et al. 2022

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Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner. Lay SummaryIn rats prenatally exposed to valproate as a model of autism, a modulator of α5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism-like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of α5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment.

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Section: Discussionmentioning

confidence: 58%

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

et al. 2022

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“…Interestingly, the Kv10.2 channel is widely expressed in the brain [ 47 , 48 ]. Frequently, pathogenic potassium channel alterations give rise to a LOF, with reduced activity resulting in changes in the resting membrane potential and the repolarisation process [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism

Galán-Vidal

Socuéllamos

Baena-Nuevo

et al. 2022

Orphanet J Rare Dis

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Background Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments. Results We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome. A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel. Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again. Conclusions By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.

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“…In mammals, Kv10 channels are composed of two isoforms: Kv10.1 and Kv10.2 (Chuang et al., 2014). The Kv10.2 (encoded by the KCNH5 gene) is widely expressed in brain, mainly distributed in the cortex, olfactory bulb, hippocampus, and thalamus, but not in the striatum and pituitary (Saganich et al., 2001), located in neurons as the main cell type (Wang et al., 2019). Kv10.2 is localized in both dendrosomatic and axonal compartments of hippocampal neurons, and modulate membrane excitability of these neurons (Chuang et al., 2014).…”

Section: Genetic Dysfunction Of Potassium Channels and Asd: From Genotypes To Phenotypesmentioning

confidence: 99%

“…Wang et al. (2019) reported that the decreased protein and mRNA expression of Kv10.2 in the hippocampus of valproic acid (VPA)‐exposed rat, which is commonly considered as one of the best validated ASD animal model. The elevated expression level of Kv10.2 could help to relieve anxiety and stereotypical behavior and improve the social and exploratory abilities of autistic model rats (Wang et al., 2019).…”

Section: Genetic Dysfunction Of Potassium Channels and Asd: From Genotypes To Phenotypesmentioning

confidence: 99%

“…Potassium channel genes are considered as one of the largest groups of genes involved in epilepsy and seizures, potassium channels are widely distributed that shape the action potential and set the resting membrane potential (Lee et al., 2014). Furthermore, potassium channels also play an important role in mediating neuronal excitability, shaping action potential waveforms, and regulating metabolism, thus further control cell activities necessary for life (Wang et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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Potassium channels and autism spectrum disorder: An overview

Cheng

Qiu

2021

Intl J of Devlp Neuroscience

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Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted, repetitive patterns of behaviors, interests, or activities. It had been demonstrated that potassium channels played a key role in regulating neuronal excitability, which was closely associated with neurological diseases including epilepsy, ataxia, myoclonus, and psychiatric disorders. In recent years, a growing body of evidence from whole‐genome sequencing and whole‐exome sequencing had identified several ASD susceptibility genes of potassium channels in ASD subjects. Genetically dysfunction of potassium channels may be involved in altered neuronal excitability and abnormal brain function in the pathogenesis of ASD. This review summarizes current findings on the features of ASD‐risk genes (KCND2, KCNQ2, KCNQ3, KCNH5, KCNJ2, KCNJ10, and KCNMA1) and further expatiate their potential role in the pathogenicity of ASD.

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Increased Expression of Kv10.2 in the Hippocampus Attenuates Valproic Acid-Induced Autism-Like Behaviors in Rats

Cited by 16 publications

References 40 publications

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism

Potassium channels and autism spectrum disorder: An overview

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