title: Adeno-associated virus (AAV) vector antisense gene transfer in vivo decreases GABA(A) alpha1 containing receptors and increases inferior collicular seizure sensitivity.
abstract: In the inferior colliculus, adeno-associated virus (AAV) vectors are capable of gene transfer and stable, long-term expression, but it remained to be shown if this in vivo gene transfer could alter focal seizure sensitivity in the inferior colliculus. Because GABA receptors directly modulate inferior collicular seizures, AAV vectors were constructed with a cytomegalovirus (CMV) promoter and a truncated, human GABA(A) alpha1 cDNA in both the sense and antisense orientations. Seven days after collicular microinjection of the sense vectors (1 microl; 3 x 10(9) particles/microl), neurons exhibited GABA(A) alpha-like immunoreactivity in amounts far exceeding endogenous concentrations. Unilateral or bilateral sense vector infusion had no effect on inferior collicular seizure parameters or on [3H]zolpidem binding. In contrast, bilateral infusion of the antisense AAV-GABA(A) alpha1 vector (1 microl; 3 x 10(8) particles/microl) caused a 137% increase in the seizure duration. Moreover, unilateral antisense vector infusion produced a localized, 48% decrease in [3H]zolpidem binding. Thus, in the inferior colliculus, antisense AAV-CMV vectors can reduce a specific receptor subunit protein and change receptor function that directly influences in vivo seizure sensitivity.
authors.affiliation: Gene Therapy Center, University of North Carolina at Chapel Hill, 27599, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.forename: T J
authors.initials: TJ
authors.lastname: McCown
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: G R
authors.initials: GR
authors.lastname: Breese
authors.forename: A L
authors.initials: AL
authors.lastname: Morrow
authors.forename: R J
authors.initials: RJ
authors.lastname: Samulski
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism; D007245:Inferior Colliculi / Q000378:metabolism / Q000502:physiology*; D007536:Isomerism; D008297:Male; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism*; D012640:Seizures / Q000209:etiology*; D000077334:Zolpidem
chemical_list: D016375:Antisense Elements (Genetics); D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem