Tag: tuberous sclerosis

Synaptic pathophysiology of 16p11.2 model mice

Many single-gene disorders linked to autism affect proteins that modulate the translation of messenger RNA into proteins that function at synapses, the junctions between neurons. A few examples are FMRP in fragile X syndrome, TSC1 and TSC2 in tuberous sclerosis complex and PTEN in Cowden syndrome. This led Mark Bear at the Massachusetts Institute of Technology and Raymond Kelleher at Massachusetts General Hospital to propose that ‘troubled translation’ is a core pathophysiological mechanism underlying autism spectrum disorders.

Regulation of cortical circuits by TSC1 in GABAergic interneurons

The overall goal of Michael Higley’s project was to elucidate the changes in synaptic connectivity caused by interneuron-specific loss of the autism-associated gene tuberous sclerosis complex 1 (TSC1). Higley and his group used electrophysiological analyses to reveal that deletion of TSC1 from a subclass of GABAergic interneurons that express the marker parvalbumin produces an increase in synaptic inhibition onto nearby excitatory pyramidal neurons. This result is surprising, as previous studies found that global deletion of TSC1 resulted in weakened inhibition and hyperexcitability in the network[ref]Bateup H.S. et al. Neuron 78, 510-522 (2013) PubMed[/ref],[ref]Bateup H.S. et al. J. Neurosci. 31, 8862-8869 (2011) PubMed[/ref]. Higley’s findings illustrate that dysfunction of autism-linked genes can produce complex and competing outcomes depending on the identity of neurons affected.

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