REVIEW ARTICLE published: 02 March 2015 doi: 10.3389/fncel.2015.00034 Update on the implication of potassium channels in autism: K+ channelautism spectrum disorder Luca Guglielmi 1*, Ilenio Servettini 1, Martino Caramia 2 , Luigi Catacuzzeno 2 , Fabio Franciolini 2 , Maria Cristina D’Adamo1 and Mauro Pessia1* 1 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy 2 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy Edited by: Autism spectrum disorders (ASDs) are characterized by impaired ability to properly Tycho M. Hoogland, Netherlands implement environmental stimuli that are essential to achieve a state of social and Institute for Neuroscience, Netherlands cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. Reviewed by: Noritaka Ichinohe, National Institute of These aspects are often accompanied by several comorbidities such as motor delay, Neuroscience – National Center of praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses Neurology and Psychiatry, Japan of autistic individuals uncovered deleterious mutations in several K+ channel types Mohamed Jaber, University of Poitiers, France strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K+ channels in ASD has been also reported. *Correspondence: + Luca Guglielmi and Mauro Pessia, For instance, loss of fragile X mental retardation protein (FMRP) results in K channels Section of Physiology and deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This Biochemistry, Department of review provides an update on direct and indirect implications of K+ channels in ASDs. Experimental Medicine, University of Perugia School of Medicine, Owing to a mounting body of evidence associating a channelopathy pathogenesis to P.leGambuli, Edificio D-Piano 1, autism and showing that nearly 500 ion channel proteins are encoded by the human 06132 San Sisto, Perugia, Italy genome, we propose to classify ASDs - whose susceptibility is significantly enhanced e-mail: [email protected]; by ion channels defects, either in a monogenic or multigenic condition - in a new category [email protected] named “channelAutism Spectrum Disorder”(channelASD; cASD) and introduce a new taxonomy (e.g., Kvx.y-channelASD and likewise Navx.y-channelASD,Cavx.y-channelASD; etc.). This review also highlights some degree of clinical and genetic overlap between K+ channelASDs and K+ channelepsies, whereby such correlation suggests that a subcategory characterized by a channelASD-channelepsy phenotype may be distinguished. Ultimately, this overview aims to further understand the different clinical subgroups and help parse out the distinct biological basis of autism that are essential to establish patient-tailored treatments. + Keywords: K channels, Kv4.2 (KCND2), Kv7.3(KCNQ3), KCa1.1 (KCNMA1), Kir2.1 (KCNJ2), Kir4.1 (KCNJ10), FMRP (FMR1), channelASD-channelepsy phenotype INTRODUCTION severity of the symptoms, ASD is thought to be caused by mul- Nearly 70 million people worldwide suffer from ASD. 700,000 are tiple factors interacting in a complex way. Genetic defects, both from USA and the estimated cost to society of caring for these chil- inherited or occurring spontaneously, undoubtedly play a role dren has been $11.5 billion in 2011 (Lavelle et al., 2014). ASD is a in increasing the susceptibility to the disorder by affecting brain group of heterogeneous neurodevelopmental disorders previously development and proper neural networking. Neurological comor- dealt with as single pathologies: autistic disorder, pervasive devel- bidities are often observed in ASD patients and they are associated opmental disorder-not otherwise specified (PDD-NOS), Asperger with more clinical severity. The most noted is epilepsy, comor- syndrome, childhood disintegrative disorder also known as Heller bid in 30% of ASD, about 50 times higher than in the general syndrome, and Rett syndrome. Specific impairments before age population (Tuchman and Rapin, 2002; Mouridsen et al., 2011). three, in each of the following three core domains fit the diagnos- Cognitive and behavioral deficits occurs in up to 46% of children tic criteria for ASD: social (difficulty in interacting with people, with epilepsy (Clarke et al., 2005; Matsuo et al., 2010) suggesting in reading facial expressions and making eye contact), language that, at least in these cases, the excitability imbalance could be a (difficulty in using or understanding language, tending to focus common denominator. Another comorbidity observed in nearly attention and conversation on a limited number of topics, fre- 90% of genetic syndromes associated with ASDs is motor delay. quently repeat phrases, and have very limited speech ability), and Delays occur in both gross and fine motor domains, while deficits restricted/repetitive behavior (excessive attention to routines and are documented in praxis, motor planning, gait, coordination, and difficulty in adjusting to new surroundings or changes in rou- postural control (Rinehart and McGinley, 2010; Van Waelvelde tine). Given the complexity of the disorder and the variety and et al., 2010). Several lines of evidence suggest that motor delay is Frontiers in Cellular Neuroscience www.frontiersin.org March 2015 | Volume 9 | Article 34 | 1 Guglielmi et al. K+ Channelautism caused by aberrant neural circuitry mostly in the cerebellum and as homomers, whenever four identical α-subunits are assem- fronto-striatal regions (Rinehart et al., 2006; Wegiel et al., 2013). bled or as heteromers, whenever different types of α-subunits The relative risk for a child to develop the disease is increased heteropolymerize to form channels with distinct functional and ∼25-fold in families in which a sibling is affected (Jorde et al., pharmacological properties (Pessia, 2004). 1991). Unfortunately, the genetic etiology of autism is character- ized by high locus heterogeneity, where de novo and rare inherited Kv4.2 – ChannelASD CNVs and SNV mutations in conjunction contribute to the over- KCND2 gene encodes for the α subunit of the voltage-gated K+ all genetic risk to develop the disease. To date, we know that channel Kv4.2 that generates an “A-type” current (IA). When defined mutations, genetic syndromes and de novo CNVs account assembled in homotetramers, Kv4.2 channels activate at sub- for about 30% of ASD cases (Schaaf and Zoghbi, 2011). Link- threshold membrane potentials, inactivate rapidly, and quickly age analyses of ASD patients have allowed the identification of recover from inactivation (Zhu et al., 1999; Birnbaum et al., 2004). loss- or gain-of-function mutations and chromosomal alterations The availability of this channel type, in response to membrane in genes coding for several channel types, including K+ chan- potential fluctuation, is regulated by its peculiar inactivation nels. These proteins are highly heterogenic and widely expressed kinetics occurring from the open state by a fast N-type mech- in the CNS where they set the resting membrane potential of anism or (much more frequently) from pre-open closed states, neurons and glia, shape action potentials and regulate firing, when the voltage-sensor domains activate but the pore fails to neurotransmitter release and wiring. At network level, K+ chan- open (Bahring et al., 2001; Gebauer et al., 2004; Jerng et al., nels are involved in post-synaptic EPSP-spike coupling, activity 2004; Barghaan and Bahring, 2009; Bahring and Covarrubias, dependent short- and long-term synaptic plasticity and informa- 2011). In vivo, other proteins further tune-up Kv4.2 inactiva- tion processing. Thus, these channels provide neurons, glia and tion kinetics: the K+ channel interacting protein (KChIP) and the CNS networks with distinct electrical identity and their dysfunc- dipeptidyl-peptidase-like protein (DPP) that respectively inhibits tion is a major contributing factor in excitability disequilibrium and accentuates N-type open state inactivation (Wang et al., 2002; and network impairment. Animal models, in which these genes Jerng et al., 2005, 2009; Covarrubias et al., 2008). This channel type are deleted or mutated, often show epilepsy (Eijkelkamp et al., is mainly expressed in the hippocampal CA1 pyramidal neurons 2012; D’Adamo et al., 2013, 2014), motor impairment, learn- where it regulates the threshold for action potential initiation and ing and behavioral phenotypes that resemble somehow ASD. repolarization, frequency-dependent AP broadening, and back- The insights, provided by investigations with these animal mod- propagation of action potentials (Chen et al., 2006; Kim et al., els, are valuable to understand neural networks abnormalities 2007; Nerbonne et al., 2008). These notions were further corrob- potentially underlying ASD. The plethora of ion channel types orated by the evidence that Kv4.2 channel deletion lowers and expressed by neurons and the numerous variations discovered increases the threshold for LTP and LTD induction, respectively in their relevant genes often generate confusion in the classi- (Chen et al., 2006; Zhao et al., 2011). Conversely, enhancement fication of the associated diseases. To further understand the of Kv4.2 expression prevents LTP induction (Jung et al., 2008). clinical subgroups of autism, help parse out distinct