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1.
Neuropsychopharmacology ; 33(3): 674-84, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17460611

RESUMO

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.


Assuntos
Antimaníacos/farmacologia , Desenvolvimento Embrionário/genética , Carbonato de Lítio/farmacologia , Agonistas Muscarínicos/farmacologia , Monoéster Fosfórico Hidrolases/genética , Pilocarpina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cromatografia Gasosa , Ingestão de Líquidos/efeitos dos fármacos , Inositol/deficiência , Inositol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Mutagênese , Monoéster Fosfórico Hidrolases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Natação/psicologia
2.
J Neurosci ; 26(46): 12055-66, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17108179

RESUMO

Uptake of L-glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). Three transporters (VGLUT1-VGLUT3) are expressed in the mammalian CNS, with partial overlapping expression patterns, and VGLUT2 is the most abundantly expressed paralog in the thalamus, midbrain, and brainstem. Previous studies have shown that VGLUT1 is necessary for glutamatergic transmission in the hippocampus, but the role of VGLUT2 in excitatory transmission is unexplored in glutamatergic neurons and in vivo. We examined the electrophysiological and behavioral consequences of loss of either one or both alleles of VGLUT2. We show that targeted deletion of VGLUT2 in mice causes perinatal lethality and a 95% reduction in evoked glutamatergic responses in thalamic neurons, although hippocampal synapses function normally. Behavioral analysis of heterozygous VGLUT2 mice showed unchanged motor function, learning and memory, acute nociception, and inflammatory pain, but acquisition of neuropathic pain, maintenance of conditioned taste aversion, and defensive marble burying were all impaired. Reduction or loss of VGLUT2 in heterozygous and homozygous VGLUT2 knock-outs led to a graded reduction in the amplitude of the postsynaptic response to single-vesicle fusion in thalamic neurons, indicating that the vesicular VGLUT content is critically important for quantal size and demonstrating that VGLUT2-mediated reduction of excitatory drive affects specific forms of sensory processing.


Assuntos
Ácido Glutâmico/metabolismo , Neuralgia/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Terminações Pré-Sinápticas/metabolismo , Vesículas Sinápticas/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/genética , Genes Letais/genética , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/genética , Neuralgia/fisiopatologia , Medição da Dor/métodos , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Transmissão Sináptica/genética , Tálamo/metabolismo , Tálamo/fisiopatologia , Tálamo/ultraestrutura , Proteína Vesicular 2 de Transporte de Glutamato/genética
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