RESUMO
LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for the ligand lysophosphatidic acid. We have investigated the effect of targeted deletion at the lpa1 locus on evoked release of amino acids from hippocampal slices, using in vitro superfusion techniques, and evoked 5-HT efflux from the dorsal raphe nucleus, using in vitro fast cyclic voltammetry. Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+ -evoked release of glutamate and GABA were significantly decreased in lpa1(-/-) mice. Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(-/-) mice. In summary, these data demonstrate that the lpa1 mutation produces a number of changes in neurotransmitters that have been associated with a schizophrenic-like pathology.
Assuntos
Química Encefálica/genética , Receptores de Ácidos Lisofosfatídicos/deficiência , Receptores de Ácidos Lisofosfatídicos/genética , Esquizofrenia/genética , Aminoácidos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Estimulação Elétrica , Feminino , Camundongos , Camundongos Knockout , Neurotransmissores/metabolismo , Núcleos da Rafe/metabolismo , Serotonina/metabolismoRESUMO
BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.