Mutations causing syndromic autism define an axis of synaptic pathophysiology

By Benjamin D. Auerbach, Emily K. Osterweil, Mark F. Bear. Nature, 2011

596 citations recorded by the source corpus.

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/227ade2a4708b1162b9fc36c66f62b2cba02ebfe

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Michael C. Schatz
2. Richard K. Wilson
3. Elaine R. Mardis
4. Jerzy K. Kulski
5. Piotr Fryzlewicz

In Molecular Biology

1. Michael C. Schatz
2. W. Richard McCombie
3. Richard K. Wilson
4. Elaine R. Mardis
5. R. Fulton
6. Vincent J. Magrini
7. R. Darnell
8. Jerzy K. Kulski

Citations in the corpus

• De Novo Gene Disruptions in Children on the Autistic Spectrum (2012, background): “Mediators of Neuroplasticity inCognitive andBehavioral Disorders FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011; Auerbach et al., 2011).”
• The Neurology of mTOR (2014, unknown): “Consistently, inhibition of protein synthesis or mTOR signaling blocks mGluR-dependent LTD (Auerbach et al., 2011; Banko et al., 2006; Hou and Klann, 2004; Huber et al., 2000).”