RESUMEN
A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.
Asunto(s)
Conducta Animal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Ácido Glutámico/metabolismo , Racemasas y Epimerasas/deficiencia , Estimulación Acústica/métodos , Anestésicos Locales/farmacología , Animales , Conducta Animal/efectos de los fármacos , Bencilaminas/farmacología , Biotina/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Antagonistas del GABA/farmacología , Hipocampo/citología , Técnicas In Vitro , Inhibición Psicológica , Lidocaína/análogos & derivados , Lidocaína/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Neuronas/fisiología , Técnicas de Placa-Clamp , Ácidos Fosfínicos/farmacología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Quinoxalinas/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiologíaRESUMEN
There is substantial evidence implicating N-methyl-D-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia as morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR-/-) mouse in which the first coding exon of the mouse SR gene has been deleted, to explore the role of D-serine in regulating cognitive functions as well as dendritic architecture. SR-/- mice exhibited a significantly disrupted representation of the order of events in distinct experiences as showed by object recognition and odor sequence tests; however, SR-/- animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR-/- mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR-/- mice displayed reductions in the complexity, total length and spine density of apical dendrites. These findings show that D-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the medial PFC (mPFC). Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.