THESIS
2018
xxi, 152 pages : illustrations (some color) ; 30 cm
Abstract
Intronic polymorphisms of the GABA
A receptor β
2 subunit gene (GABRB2) were earlier
associated with schizophrenia, deficit of gene expression, different electrophysiological
properties of the long and short isoforms, and identification of both preventive and causative
haplotypes. Herein, gene dosage effects of Gabrb2 were examined in knockout mice of both
heterozygous (HT) and homozygous (KO) genotypes.
Gabrb2-knockout HT and KO mice were evaluated for schizophrenia-like phenotypes and
comorbidities employing animal behavioral tests. Neural alterations in these mice were studied
using biochemical and immunohistochemical assays. The KO mice, and HT mice to a lesser
extent, were found to display prepulse inhibition deficit, locomotor hyperactivity, stereotypy,
sociability impairme...[
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Intronic polymorphisms of the GABA
A receptor β
2 subunit gene (GABRB2) were earlier
associated with schizophrenia, deficit of gene expression, different electrophysiological
properties of the long and short isoforms, and identification of both preventive and causative
haplotypes. Herein, gene dosage effects of Gabrb2 were examined in knockout mice of both
heterozygous (HT) and homozygous (KO) genotypes.
Gabrb2-knockout HT and KO mice were evaluated for schizophrenia-like phenotypes and
comorbidities employing animal behavioral tests. Neural alterations in these mice were studied
using biochemical and immunohistochemical assays. The KO mice, and HT mice to a lesser
extent, were found to display prepulse inhibition deficit, locomotor hyperactivity, stereotypy,
sociability impairments, spatial-working and spatial-reference memory deficits, reduced
depression and anxiety, and accelerated pentylenetetrazol-induced seizure. In addition, the KO
mice were highly susceptible to audiogenic epilepsy. Some of the schizophrenia-like phenotypes
and comorbidities showed evidence of imprinting, gender effect and amelioration by the
antipsychotic risperidone, whereas the audiogenic epilepsy was inhibited by the antiepileptic
diazepam.
GABAergic parvalbumin-positive interneuron dystrophy, astrocyte dystrophy and extensive
microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of
newborn neurons was observed in the hippocampus by immunohistochemical staining. The
neuroinflammation suggested by microglial activation was also indicated by elevated brain levels
of oxidative stress marker malondialdehyde and the pro-inflammatory cytokines tumor necrosis
factor-alpha and interleukin-6.
The extensive schizophrenia-like phenotypes and comorbidities brought about by Gabrb2
knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia,
provided evidence for a GABRB2-origin hypothesis of schizophrenia.
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