Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts

The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala

In rodents, the medial nucleus of the amygdala receives direct inputs from the accessory olfactory bulbs and is mainly implicated in pheromone-mediated reproductive and defensive behaviors. The principal neurons of the medial amygdala are GABAergic neurons generated principally in the caudo-ventral medial ganglionic eminence and preoptic area. Beside GABAergic neurons, the medial amygdala also contains glutamatergic Otp-expressing neurons cells generated in the lateral hypothalamic neuroepithelium and a non-well characterized Pax6-positive population. In the present work, we describe a novel glutamatergic Ebf3-expressing neuronal subpopulation distributed within the periphery of the postero-ventral medial amygdala. These neurons are generated in a pallial domain characterized by high expression of Gdf10. This territory is topologically the most caudal tier of the ventral pallium and accordingly, we named it Caudo-Ventral Pallium (CVP). In the absence of Pax6, the CVP is disrupted and Ebf3-expressing neurons fail to be generated. Overall, this work proposes a novel model of the neuronal composition of the medial amygdala and unravels for the first time a new novel pallial subpopulation originating from the CVP and expressing the transcription factor Ebf3.This work was supported by Grants of the French National Research Agency (Agence Nationale de la Recherche; ANR) [ANR-13-BSV4-0011] and by the French Government through the ‘Investments for the Future’ LABEX SIGNALIFE [ANR-11-LABX-0028-01] to M.S., by the Spanish Government (BFU2007-60263 and BFU2010-17305) to A.F, and by the Medical Research Council (MR/K013750/1) to T.T. N.R.-R. is funded by a postdoctoral fellowship from the Ville de Nice, France (“Aide Individuelle aux Jeunes Chercheurs 2016”).Peer reviewe

Cerebroglycan, a Developmentally Regulated Cell-Surface Heparan Sulfate Proteoglycan, Is Expressed on Developing Axons and Growth Cones

Cerebroglycan is a glycosylphosphatidylinositol-linked integral membrane heparan sulfate proteoglycan found exclusively in the developing nervous system. In the rodent, cerebroglycan mRNA first appears in regions containing newly generated neurons and typically disappears 1 to several days later (Stipp et al., 1994, J. Cell Biol. 124:149-160). To gain insight into the roles that cerebroglycan plays in the developing nervous system, monospecific antibodies were prepared and used to localize cerebroglycan protein. In the rat, cerebroglycan was prominantly expressed on axon tracts throughout the developing brain and spinal cord, where it was found at times when axons are actively growing, but generally not after axons have reached their targets. Cerebroglycan was also found on neuronal growth cones both in vivo and in vitro. Interestingly, cerebroglycan immunoreactivity was rarely seen in or around neuronal cell bodies. Indeed, by examining the hippocampus at a late stage in development-when most neurons no longer express cerebroglycan but newly generated granule neurons do-evidence was obtained that cerebroglycan is strongly polarized to the axonal, and excluded from the somatodendritic, compartment of neurons. The timing and pattern of cerebroglycan expression are consistent with a role for this cell-surface heparan sulfate proteoglycan in regulating the growth or guidance of axons

Associations between Quantitative Sleep EEG Data and Subsequent Cognitive Decline in Community-Dwelling Older Women

Introduction: Healthy aging is associated with changes in both circadian and homeostatic sleep regulatory processes as well as a higher prevalence of sleep disorders, which in turn can accelerate the aging process and increase the risk for cognitive impairment. EEG power spectrum can provide additional information regarding the memory consolidation processes compared to the traditional sleep scoring. This study examined whether quantitative sleep EEG traits predict development of mild cognitive impairment (MCI) and/or incident dementia. Methods: Participants consisted of a randomly selected subgroup of women (mean age 83 yrs) from the Sleep and Cognition Study, an ancillary study to the longitudinal Study of Osteoporotic Fractures (SOF), who were free of cognitive impairment at the time of a baseline polysomnography study (SOF Visit 8). Cases (n=85) were women who developed mild MCI or dementia by objective testing at an exam 4 years after polysomnography. Controls were those with no MCI/Dementia (n=85). Absolute power for EEG frequency bands were generated using off-line spectral analysis based on a Fast-Fourier Transform (FFT) Routine (Vitascore, TEMEC). Results: At Visit 8, groups did not differ in age, BMI, education, co-morbidities, subjective sleepiness, sleep architecture as well as respiratory disturbance, arousal and periodic limb movement indices. Differences in EEG power density during nonREM sleep were observed over a broad frequency range, with higher values in the Dementia/MCI group particularly in the alpha band (8-12Hz;p=0.003), but also in the sigma (12-15Hz;p=0.04) and theta (4-8Hz;p=0.03) bands, and for slow wave activity (0.75-4.5Hz) during the first 2 hours of sleep (p=0.02) and during hours 4 and 6 (p=0.01). Conclusion: Our study provides evidence for quantitative EEG changes, which precede the onset of cognitive decline and the diagnosis of dementia in elderly women. Whether the observed differences are functionally related to neurodegenerative changes or represent unspecific EEG alterations remains to be investigated. Support (if any) NIH grant # K23HL103850 (ID