Develpmental seizures and mortality result from reducing GABAA receptor alpha2-subunit interaction with collybistin
Articolo
Data di Pubblicazione:
2018
Abstract:
Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors
(GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain
unclear. Using isothermal titration calorimetry and complementary methods we demonstrate
an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore
the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a
mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss
of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic
currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility
to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in
electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective
positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit
selective binding of collybistin, which plays a key role in patterned brain activity, particularly
during development.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
inhibitory synaptic
GABAARs
Gabra2–1 mice
Elenco autori:
Hines RM, Maric HM, Hines DJ, Modgil A, Panzanelli P, Nakamura Y, Nathanson AJ, Cross A, Deeb T, Brandon NJ, Davies P, Fritschy JM, Schindelin H, Moss SJ.
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