ABSTRACT
Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (Tg-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients with schizophrenia.
Subject(s)
Antipsychotic Agents/therapeutic use , Disease Models, Animal , Glycine N-Methyltransferase/metabolism , Metencephalon/drug effects , Neurons/drug effects , Schizophrenia/drug therapy , Animals , Clozapine/therapeutic use , Crosses, Genetic , Gene Expression Regulation/drug effects , Glycine N-Methyltransferase/genetics , Humans , Male , Metencephalon/metabolism , Metencephalon/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Organ Specificity , RNA, Messenger/metabolism , Sarcosine/metabolism , Sarcosine/therapeutic use , Schizophrenia/metabolism , Schizophrenia/pathology , Signal Transduction/drug effectsABSTRACT
New generation antiepileptic drugs, including gabapentin and tiagabine, are used in monotherapy or in combination with other drugs for specific seizure types. The multidirectional mechanism of activity and varied pharmacological properties of these drugs suggest that they could also be used in the therapy of other diseases. A possible limitation of new generation antiepileptic drugs is the incidence of CNS-related adverse effects. Few studies have assessed the effect of new antiepileptic drugs on electroencephalogram (EEG) recordings in subjects using these drugs for diseases other than epilepsy. The aim of this study was to determine the effects of tiagabine and gabapentin on EEG recordings from the midbrain reticular formation, dorsal hippocampus and frontal cortex in rabbits. Tiagabine was administered orally at a single dose of 5 and 20 mg kg(-1), or repeatedly at a dose of 5 mg kg(-1) (twice a day) for 14 days. Gabapentin was administered orally at a single dose of 25 and 100 mg kg(-1), or repeatedly at a dose of 25 mg kg(-1) (twice a day) for 14 days. Both tiagabine and gabapentin caused changes indicative of CNS inhibitory properties, which may be associated with the adverse effects of the drugs. After repeated doses of the drugs, the changes in EEG recordings were less pronounced than after single doses, which may indicate adaptive changes. The hippocampus was found to be the least sensitive to the effect of gabapentin.
Subject(s)
Amines/pharmacology , Anticonvulsants/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Electroencephalography/drug effects , Nipecotic Acids/pharmacology , gamma-Aminobutyric Acid/pharmacology , Amines/administration & dosage , Animals , Anticonvulsants/administration & dosage , Cyclohexanecarboxylic Acids/administration & dosage , Dose-Response Relationship, Drug , Female , Frontal Lobe/drug effects , Gabapentin , Hippocampus/drug effects , Male , Metencephalon/drug effects , Nipecotic Acids/administration & dosage , Rabbits , Tiagabine , gamma-Aminobutyric Acid/administration & dosageABSTRACT
The effects of phalloidin, a preperation which highly specifically and selectively polymerizes actin and which binds to actin, on the electrotonic conductivity and structure of mixed synapses were studied in goldfish Mauthner neurons (MN). These experiments showed that paired subthreshold electrical stimulation of the afferent input in the presence of phalloidin led to increases in the amplitude of MN responses to the second stimulus by an average of 80%. In controls, this amplitude increased by only 10% and only when suprathreshold stimuli were used, while subthreshold stimuli were ineffective. We regard these results as demonstrating increases in the conductivity of mixed synapses, this being induced by polymerization of actin. At the ultrastructural level, application of phalloidin to MN and their mixed synapses induced increases in the sizes and numbers of actin-containing desmosome-like contacts, and in the numbers of fibrillar bridges in the clefts of these contacts. Use of colloidal gold as a label for phalloidin demonstrated that bridges were made of actin. The interdependent morphofunctional changes seen in mixed synapses provide grounds for suggesting a role for actin in the conduction of the electrotonic signal through mixed synapses. The structural substrate for this process may be provided by bridges in the clefts of desmosome-like contacts.
