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Südhof, T.

Publications and source records attributed to Südhof, T..

2 recordsLinked to original sources

Astrocytic Neuroligins Are Not Required for Synapse Formation or a Normal Astrocyte Cytoarchitecture

Astrocytes perform multifarious roles in the formation, regulation, and function of synapses in the brain, but the mechanisms involved are incompletely understood. Interestingly, astrocytes abundantly express neuroligins, postsynaptic adhesion molecules that function as synaptic organizers by binding to presynaptic neurexins. Here we examined the function of neuroligins in astrocytes with a rigorous genetic approach that uses the conditional deletion of all major neuroligins (Nlgn1-3) in astrocytes in vivo and complemented this approach by a genetic deletion of neuroligins in glia cells that are co-cultured with human neurons. Our results show that early postnatal deletion of neuroligins from astrocytes in vivo has no detectable effect on cortical or hippocampal synapses and does not alter the cytoarchitecture of astrocytes when evaluated in young adult mice. Moreover, deletion of astrocytic neuroligins in co-cultures of human neurons produced no detectable consequences for the formation and function of synapses. Thus, astrocytic neuroligins are unlikely to fundamentally shape synapse formation or astrocyte morphogenesis but likely perform other important roles that remain to be discovered.

neuroscience↗

ApoE2, ApoE3 and ApoE4 Differentially Impact Multiple Signaling Pathways Regulating Synaptogenesis

Apolipoprotein E (ApoE) mediates clearance of circulating lipoproteins from blood by binding to ApoE receptors. Humans express three genetic variants, ApoE2, ApoE3, and ApoE4, that exhibit distinct ApoE receptor binding properties. In brain, ApoE is abundantly produced by activated astrocytes and microglia, and three variants differentially affect Alzheimers disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to the disease. A role for ApoE4 in driving microglial dysregulation and impeding A{beta} clearance in AD is well documented, but the direct effects of three variants on neurons are poorly understood. Extending previous studies, we here demonstrate that ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades which among others enhance synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted paracrine signal and activates neuronal signaling pathways in what may represent a protective response, with the differential potency of ApoE variants causing distinct levels of chronic signaling that may contribute to AD pathogenesis.

molecular biology↗