Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Abstract

SummaryMaternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.

T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains

“…29 By contrast, ASD Case A1 (mutations in ARID1B, CACNA1C, and SLC6A8), ASD Case A3 (mutation in SETD2), ASD Case A5 (dup15q), and another~30% of the ASD cases that are genetically undefined lacked features of the T-lymphocyte and astroglial neuropathology, suggesting behavioral deficits in these genetic subsets of ASD might instead arise from direct effects of the genetic or epigenetic changes on the neuronal circuits controlling behaviors impaired in ASD. [30][31][32][33][34][35][36] CD8 + T-lymphocyte infiltrates and cytotoxic astrocyte membranous blebs represent a new cellular process not previously reported in studies of ASD neuropathology. [37][38][39][40][41] Future research should test whether the maternal-fetal [42][43][44][45][46][47][48][49][50][51] or autoimmune [52][53][54][55] antibodies found in the serum in some cases of ASD co-occur with the CD8 + T-lymphocyte immune cell infiltrates and astrocyte membranous blebs or represent a separate autoimmune subtype of ASD.…”

“…Similarly, XYY is a genetic defect reported in ASD cohorts, and genes on the Y chromosome have been connected to an increased risk of immunologic disease . By contrast, ASD Case A1 (mutations in ARID1B , CACNA1C , and SLC6A8 ), ASD Case A3 (mutation in SETD2 ), ASD Case A5 (dup15q), and another ~30% of the ASD cases that are genetically undefined lacked features of the T‐lymphocyte and astroglial neuropathology, suggesting behavioral deficits in these genetic subsets of ASD might instead arise from direct effects of the genetic or epigenetic changes on the neuronal circuits controlling behaviors impaired in ASD …”

Glial overexpression of Dube3a causes seizures and synaptic impairments in Drosophila concomitant with down regulation of the Na+/K+ pump ATPα

“…This is the first model of Dup15q syndrome that recapitulates the seizure phenotype observed in Dup15q individuals as currently available mouse models do not develop epilepsy (Nakatani et al, 2009, Smith et al, 2011, Krishnan et al, 2017). Dup15q mouse models have thus far focused on overexpression of Ube3a in neurons, since Ube3a is only imprinted in neurons while glia, which biallelically express Ube3a , have been largely ignored.…”

“…Another mouse model duplicating only Ube3a recapitulated deficits in social interaction, social communication, and increased repetitive behavior but it is likely that the addition of a 3xFLAG tag to the C-terminus of Ube3a rendered the ubiquitin ligase activity of Ube3a-FLAG protein non-functional (Smith et al, 2011). More recently, overexpression of Ube3a limited to neurons was not associated with seizures in mice but was linked to seizure-induced decreased sociability (Krishnan et al, 2017). Elevated levels of Ube3a in excitatory neurons in mice caused increased anxiety-like behaviors, cognitive impairments, and reduced seizure threshold to pharmacologically induced seizures with pentylenetetrazol, however spontaneous seizures have not been observed in these mice (Copping et al, 2017).…”

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

“…Diffraction data for NP1PTX were collected at Diamond Light Source (DLS) beamline I03 to a nominal resolution of 1.45 Å in space group (SG) C2. All data were indexed, integrated, and scaled using the automated XIA2 expert system (16), using the Labelit (17), POINTLESS and AIMLESS 150 (18,19), and XDS (20) programs. The structure of NP1PTX was solved by molecular replacement using the program Phaser (21) and using the human SAP (Serum Amyloid P Component; PDB code 1SAC) crystal structure (22) as a search model.…”