Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome.

Abstract

The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABA(A) receptor agonist, bretazenil, or a GABA(A) α2/α3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of Comt to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both Comt overexpression and Comt inhibition caused an abnormal responsiveness to Bretazenil, a GABA(A) receptor agonist in control mice. Comt overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as Gabrb2 (GABA(A)receptor β2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a Comt expression level in PFC. Our data suggest that Comt-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice.

• Authors: S Kimoto, K Muraki, M Toritsuka, S Mugikura, K Kajiwara, T Kishimoto, E Illingworth, K Tanigaki
• Journal: Translational psychiatry (Transl Psychiatry) Vol. 2 Pg. e146 (Aug 07 2012) ISSN: 2158-3188 [Electronic] United States
• PMID: 22872161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzodiazepinones
• Dopamine Agonists
• GABA-A Receptor Agonists
• Receptors, N-Methyl-D-Aspartate
• Reelin Protein
• gamma-Aminobutyric Acid
• Catechol O-Methyltransferase
• Reln protein, mouse
• bretazenil
• Dopamine

Topics

• Animals
• Benzodiazepinones (pharmacology)
• Catechol O-Methyltransferase (genetics, metabolism)
• Chromatography, High Pressure Liquid
• DiGeorge Syndrome (genetics)
• Disease Models, Animal
• Dopamine (analysis)
• Dopamine Agonists (pharmacology)
• GABA-A Receptor Agonists (pharmacology)
• Gene Expression
• Mice
• Mice, Knockout
• Prefrontal Cortex (enzymology)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Reelin Protein
• Reverse Transcriptase Polymerase Chain Reaction
• Schizophrenia (genetics)
• gamma-Aminobutyric Acid (analysis)