Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation.

Intronic polymorphisms of the GABAA receptor ß2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of Gabrb2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-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 indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by Gabrb2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.

Antiaging and Anxiolytic Effects of Combinatory Formulas Based on Four Medicinal Herbs.

The objective of the present study was to search for medicinal-herb combinations based on Radix Bupleurum chinense DC ("B"), Rhizoma Corydalis yanhusuo WT Wang ("Y"), Caulis Polygonum multiflorum Thunb ("P"), and Flos Albizia julibrissin Durazz ("A") for antiaging, anxiolytic, and sedative effects. Application of the D-galactose induced accelerated-aging model employing male ICR mice showed that oral administration of some combinations of B, Y, P, and A significantly improved spatial memory in Y-maze test and reduced brain levels of tumor necrosis factor-α and interleukin-6 based on immunoassays and oxidative stress marker malondialdehyde, based on the thiobarbituric acid test, and the loss of whiskers, indicating antiaging and antineurodegeneration effects. In addition, some of the combinatory formulas induced anxiolysis measured using the elevated plus-maze test and/or sedative effects measured using the hole-board test. Over the range of dosages examined, all possible combinations of the four herbs were devoid of any significant side effects in the form of altered locomotor activity, decreased muscle coordination, or anterograde amnesia assessed using the photobeam and rotarod and step-through passive avoidance methods, respectively. The results suggest that various combinations of the B, Y, P, and A herbs could be useful as nonsedative, antiaging and/or antineurodegenerative agents, or anxiolytic agents.