Here we describe an important involvement of Cdk5/p35 in regulating the gene expression of acetylcholine receptor (AChR) at the neuromuscular synapse. Cdk5 and p35 were prominently expressed in embryonic muscle, and concentrated at the neuromuscular junction in adulthood. Neuregulin increased the p35-associated Cdk5 kinase activity in the membrane fraction of cultured C2C12 myotubes. Co-immunoprecipitation studies revealed the association between Cdk5, p35 and ErbB receptors in muscle and cultured myotubes. Inhibition of Cdk5 activity not only blocked the NRG-induced AChR transcription, but also attenuated ErbB activation in cultured myotubes. In light of our finding that overexpression of p35 alone led to an increase in AChR promoter activity in muscle, Cdk5 activation is sufficient to mediate the up-regulation of AChR gene expression. Taken together, these results reveal the unexpected involvement of Cdk5/p35 in neuregulin signaling at the neuromuscular synapse.

Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5͞p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin͞ErbB signaling in myotube culture. To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5 ؊/؊ mice was examined. Consistent with our previous demonstration that Cdk5 phosphorylates ErbB2͞3 to regulate its tyrosine phosphorylation, we report here that the phosphorylation of ErbB2 and ErbB3 and the ErbB2 kinase activity are reduced in Cdk5-deficient muscle. In addition, Cdk5 ؊/؊ mice also display morphological abnormalities at the NMJ pre-and postsynaptically. Whereas the outgrowth of the main nerve trunk is grossly normal, the intramuscular nerve projections exhibit profuse and anomalous branching patterns in the Cdk5 ؊/؊ embryos. The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5 ؊/؊ diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages. Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed. These abnormalities are accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Taken together, our findings reveal the essential role of Cdk5 in regulating the development of motor axons and neuromuscular synapses in vivo.agrin ͉ Cdk5 ͉ ErbB receptor ͉ neuromuscular junction

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Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications ( DAAM1 and THBS3 ), or close to genes causing Mendelian brain-related diseases ( ZIC4 and FGFRL1 ). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

There have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS—and its main symptom dimensions—influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy—the same SNP affecting two traits—and concordance—the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10−4) and caudate (p = 4 × 10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10−3). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10−3), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10−7) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Highlights Little work on the concordance of genetic variation between PTSD or anxiety disorders and brain volume has been conducted  There is evidence for genome wide concordance between genetic risk factors for anxiety disorders and smaller amygdala volume  A genetic variant that contributes to both reduced putamen volume and PTSD plays a key role in the glutamatergic system  Larger sample sizes will enhance statistical power in future iterations of this analysis