Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction, communication skills, and restricted and repetitive behavior. The genetic causes for autism are largely unknown. Previous studies implicate CACNA1C (L-type Ca V 1.2) calcium channel mutations in a disorder associated with autism (Timothy syndrome). Here, we identify missense mutations in the calcium channel gene CACNA1H (T-type Ca V 3.2) in 6 of 461 individuals with ASD. These mutations are located in conserved and functionally relevant domains and are absent in 480 ethnically matched controls (p ‫؍‬ 0.014, Fisher's exact test). Non-segregation within the pedigrees between the mutations and the ASD phenotype clearly suggest that the mutations alone are not responsible for the condition. However, functional analysis shows that all these mutations significantly reduce Ca V 3.2 channel activity and thus could affect neuronal function and potentially brain development. We conclude that the identified mutations could contribute to the development of the ASD phenotype.Autism spectrum disorders affect ϳ0.5% of children in the general population and cause great morbidity (1, 2). Epidemiologic studies estimate that up to 400,000 children are affected in the United States alone (3). The primary features of ASD are severe difficulties in social interaction, communication deficits, and unusual behaviors, including repetitive and/or ritualistic actions. There is considerable variation in the severity of phenotypes in autism spectrum disorders, which include autism, Asperger syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified. Despite the high prevalence and importance of autism spectrum disorders, very little is known about underlying molecular and cellular mechanisms (4).Timothy syndrome (TS) 3 is a complex physiological and developmental disorder, which includes autism spectrum disorders. We discovered that TS resulted from a recurrent, de novo CACNA1C calcium (Ca 2ϩ ) channel mutation, G406R. Our findings that individuals with TS met the criteria for autism, or had severe deficits of language and social development, suggest that abnormal Ca 2ϩ signaling may cause these disorders (5). Based on these results we hypothesized that mutations in other Ca 2ϩ channel genes might be responsible for non-syndromic forms of ASD.Neuroanatomical studies of autistic patients have found histological abnormalities in the major regions of the limbic system including the hippocampus and amygdala and in the cerebellum and cerebral cortex (6). Ca V 3.2, a T-type calcium channel encoded by the CACNA1H gene, is abundantly expressed in these and other regions. T-type Ca 2ϩ channels activate with relatively small depolarization of the neuron membrane triggering low threshold spikes that contribute to rebound burst firing and oscillatory behavior in central neurons (7). In the thalamus, this behavior maintains normal transitions in sensory gating, sleep, and arousal (8,...

The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence, and severity. This effect is retained in cnr1−/− or cnr2−/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of Juvenile Huntington’s disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.

Cannabinoid receptor 1 (CB1 receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB1 expression in the basal ganglia of patients with Huntington’s disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB1 signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB1 downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi-quantitative immunohistochemistry, we confirmed previous studies showing that CB1 expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB1 is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB1 downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, HdhQ150/Q150 mice and the caudate nucleus of patients with HD. In R6/2 mice, CB1 downregulation in NPY/nNOS-expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro-survival signaling molecule cAMP response element-binding protein in NPY/nNOS-expressing interneurons. Loss of CB1 signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.

The transcription factor MYC (also c-Myc) induces histone modification, chromatin remodeling, and the release of paused RNA polymerase to broadly regulate transcription. MYC is subject to a series of post-translational modifications that affect its stability and oncogenic activity, but how these control MYC's function on the genome is largely unknown. Recent work demonstrates an intimate connection between nuclear compartmentalization and gene regulation. Here, we report that Ser62 phosphorylation and PIN1-mediated isomerization of MYC dynamically regulate the spatial distribution of MYC in the nucleus, promoting its association with the inner basket of the nuclear pore in response to proliferative signals, where it recruits the histone acetyltransferase GCN5 to bind and regulate local gene acetylation and expression. We demonstrate that PIN1-mediated localization of MYC to the nuclear pore regulates MYC target genes responsive to mitogen stimulation that are involved in proliferation and migration pathways. These changes are also present at the chromatin level, with an increase in open regulatory elements in response to stimulation that is PIN1-dependent and associated with MYC chromatin binding. Taken together, our study indicates that post-translational modification of MYC controls its spatial activity to optimally regulate gene expression in response to extrinsic signals in normal and diseased states.