ABSTRACT
Schizophrenia postmortem brain is characterized by gamma aminobutyric acid downregulation and by decreased dendritic spine density in frontal cortex. Protracted L-methionine treatment exacerbates schizophrenia symptoms, and our earlier work (Tremolizzo et al. and Dong et al.) has shown that L-methionine decreases reelin and GAD67 transcription in mice which is prevented by co-administration of valproate. In this study, we observed a decrease in spine density following L-methionine treatment, which was prevented by co-administration of valproate. Together with our earlier findings conducted under the same experimental conditions, we suggest that downregulation of spine density in L-methionine-treated mice may be because of the decreased expression of reelin and that valproate may prevent spine downregulation by inhibiting the methylation induced decrease in reelin.
Subject(s)
Dendritic Spines/drug effects , Dendritic Spines/pathology , Frontal Lobe/drug effects , Frontal Lobe/pathology , Methionine/toxicity , Schizophrenia/pathology , Animals , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Cell Adhesion Molecules, Neuronal/drug effects , Cell Adhesion Molecules, Neuronal/metabolism , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Shape/drug effects , Cell Shape/physiology , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Drug Interactions/physiology , Extracellular Matrix Proteins/drug effects , Extracellular Matrix Proteins/metabolism , Frontal Lobe/physiopathology , GABA Agents/pharmacology , GABA Agents/therapeutic use , Male , Methionine/metabolism , Methylation/drug effects , Mice , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Neurotoxins/metabolism , Neurotoxins/toxicity , Reelin Protein , Schizophrenia/chemically induced , Schizophrenia/physiopathology , Serine Endopeptidases/drug effects , Serine Endopeptidases/metabolism , Synapses/drug effects , Synapses/pathology , Valproic Acid/pharmacology , Valproic Acid/therapeutic useABSTRACT
Allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of GABA action at GABA(A) receptors. ALLO and THDOC are synthesized in the brain from progesterone or deoxycorticosterone, respectively, by the sequential action of two enzymes: 5alpha-reductase (5alpha-R) type I and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). This study evaluates 5alpha-R type I and 3alpha-HSD mRNA expression level in mouse brain by using in situ hybridization combined with glutamic acid decarboxylase 67/65, vesicular glutamate transporter 2, glial fibrillary acidic protein, and S100beta immunohistochemistry. We demonstrate that 5alpha-R type I and 3alpha-HSD colocalize in cortical, hippocampal, and olfactory bulb glutamatergic principal neurons and in some output neurons of the amygdala and thalamus. Neither 5alpha-R type I nor 3alpha-HSD mRNAs are expressed in S100beta- or glial fibrillary acidic protein-positive glial cells. Using glutamic acid decarboxylase 67/65 antibodies to mark GABAergic neurons, we failed to detect 5alpha-R type I and 3alpha-HSD in cortical and hippocampal GABAergic interneurons. However, 5alpha-R type I and 3alpha-HSD are significantly expressed in principal GABAergic output neurons, such as striatal medium spiny, reticular thalamic nucleus, and cerebellar Purkinje neurons. A similar distribution and cellular location of neurosteroidogenic enzymes was observed in rat brain. Taken together, these data suggest that ALLO and THDOC, which can be synthesized in principal output neurons, modulate GABA action at GABA(A) receptors, either with an autocrine or a paracrine mechanism or by reaching GABA(A) receptor intracellular sites through lateral membrane diffusion.