Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.

No abstract

No abstract

No abstract

No abstract

No abstract

BackgroundDuring the COVID-19 pandemic, many people refrained from going out, started working from home (WFH), and suspended work or lost their jobs. This study examines how such pandemic-related changes in work and life patterns were associated with depressive symptoms.MethodsAn online survey among participants who use a health app called CALO mama was conducted from 30 April to 8 May 2020 in Japan. Participants consisted of 2846 users (1150 men (mean age=50.3) and 1696 women (mean age=43.0)) who were working prior to the government declaration of a state of emergency (7 April 2020). Their daily steps from 1 January to 13 May 2020 recorded by an accelerometer in their mobile devices were linked to their responses. Depressive symptoms were assessed using the Two-Question Screen.ResultsOn average, participants took 1143.8 (95% CI −1557.3 to −730.2) fewer weekday steps during the declaration period (from 7 April to 13 May). Depressive symptoms were positively associated with female gender (OR=1.58, 95% CI 1.34 to 1.87), decreased weekday steps (OR=1.22, 95% CI 1.03 to 1.45) and increased working hours (OR=1.73, 95% CI 1.32 to 2.26). Conversely, starting WFH was negatively associated with depressive symptoms (OR=0.83, 95% CI 0.69 to 0.99).ConclusionsDecreased weekday steps during the declaration period were associated with increased odds of depressive symptoms, but WFH may mitigate the risk in the short term. Further studies on the longitudinal effects of WFH on health are needed.

*Mdga1, encoding a GPI-anchored immunoglobulin superfamily molecule containing an MAM domain, is expressed by a specific subset of neurons, including layer II/III projection neurons, in the mouse neocortex. To investigate the function of Mdga1 in corticogenesis, we generated Mdga1-deficient mice and backcrossed them to obtain a congenic background. Gross anatomy of the Mdga1-deficient brain at postnatal day (P) 14 showed no obvious phenotype. However, the migration of Mdga1-mutant neurons to the superficial cortical plate was clearly delayed. Most Mdga1-mutant neurons reached the lower portion of the upper cortical layer by embryonic day 18.5 and stayed there through P0. By P7, the location of the mutant cells was the same as wild-type. The location of Cux2-expressing upper-layer neurons in the cortical plate was largely unaffected. These observations indicated that Mdga1 is involved in the migration and positioning of a subset of cortical neurons and suggested that the radial migration of upper-layer neurons might be differentially regulated. Developmental Dynamics 240:96-107,