β3 phosphorylation in autism spectrum disorders and neurosteroid activity.
in GABAAR β3 expression and function are linked to autism spectrum disorders
(ASDs). Protein kinase C (PKC)-mediated phosphorylation of the β3 subunit on
serine residues 408/9 (S408/9) shapes its membrane expression and GABAergic inhibition.
To evaluate whether dysregulation of this process was involved in ASDs we assessed
β3 phosphorylation in Fmr1 knockout mice, a wide... read morely accepted model of ASDs. The
Fmr1 knockout mouse is a mouse model for Fragile X syndrome, a genetic disorder
involving the Fmr1 gene caused by an expansion of unstable trinucleotide repeats that
result in decreased or abolished FMRP protein expression. Fmr1 knockout mice exhibited
an increase in S408/9 phosphorylation and phasic inhibition along with significant
deficits in tonic inhibition. In transgenic S408/9A knock-in mice where S408/9 were
mutated to alanines, parallel modifications in GABAergic inhibition were observed. In
addition, S408/9A mice exhibited an increase in dendritic spine morphology, increased
repetitive-like behavior, and deficits in social interaction, prominent features of
ASDs. Our findings suggest that changes in β3 phosphorylation may contribute to
the pathophysiology of ASDs. Along with influencing GABAAR expression and function,
PKC-mediated phosphorylation has been associated with neurosteroid action on
extrasynaptic GABAARs that mediate tonic inhibition. In the dentate gyrus region of the
hippocampus, tonic inhibition is mediated by GABAARs composed of α4β3δ
subunits. Previously, we established that the neurosteroid
allotetrahydrodeoxycorticosterone (THDOC) increased the PKC-dependent phosphorylation of
α4 which led to an increase in its surface accumulation and tonic conduction. In
S408/9A mice the THDOC-mediated increase in α4 surface expression and tonic
conduction were abolished. Additionally, the anticonvulsant and hypnotic/anesthetizing
properties of THDOC were diminished in S408/9A mice compared to WT controls.
Collectively, our findings suggest a critical role for β3 phosphorylation in
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Stephen Moss.
Committee: Jamie Maguire, Chris Dulla, Margery Beinfeld, Paul Davies, and David Clapham.
Keywords: Neurosciences, and Pharmacology.read less