An amino acid motif within the GABAA receptor alpha2 subunit promotes inhibitory synaptogenesis and seizure resilience.
Nathanson, Anna.
2019
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The efficacy of
inhibitory neurotransmission is dependent on the accumulation of specific synaptic GABAA
receptor (GABAAR) subtypes at the appropriate synaptic sites. To assess the role of a 15
amino acid motif found in the intracellular loop domain (ICD) of the GABAAR alpha2
subunit in selective inhibitory synaptogenesis, I generated a novel mouse model in which
this alpha2 ICD motif has been ... read moreknocked-in to the alpha1 subunit (Gabra1-2). This
mutation leads to an enhanced in vivo interaction between the chimeric alpha1 subunit
and the inhibitory synapse proteins collybistin and gephyrin and is sufficient to target
alpha1-GABAARs to axo-axonic synapses at the axon initial segment. The Gabra1-2 mutation
also constitutes an inhibitory synapse targeting motif, causing the over-accumulation of
alpha1-GABAARs at synapses in the soma and dendrites, resulting in larger inhibitory
synaptic currents. Gabra1-2 mice display an anxiolytic phenotype, alterations in
baseline network oscillations, and decreased susceptibility to kainate-induced seizures.
In addition, the Gabra1-2 mutation is able to rescue the spontaneous seizure and early
postnatal death phenotype found in the previously described Gabra2-1 mouse, which lacks
inhibitory synapses at the AIS. Taken together, my results demonstrate that the presence
of the alpha2 ICD motif allows for subtype-selective binding of its GABAAR to
collybistin and aggregation of the receptor in the inhibitory synaptic space. Increased
synaptic clustering of the chimeric alpha1-GABAARs alters inhibitory neurotransmission
and confers resilience to ictogenesis, demonstrating that manipulating the selective
targeting of GABAAR subtypes may represent a novel therapeutic strategy to treat
epilepsy.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Neuroscience.
Advisor: Stephen Moss.
Committee: Elif Engin, Jamie Maguire, Klaus Miczek, and Thomas Biederer.
Keyword: Neurosciences.read less - ID:
- 02871840q
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