RESUMEN
The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia.
Asunto(s)
Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica/fisiología , Hipocampo/citología , Neuronas/metabolismo , Transducción de Señal/fisiología , Animales , Proteínas Bacterianas/genética , Biofisica , Células Cultivadas , Clatrina/farmacología , Disbindina , Proteínas Asociadas a la Distrofina , Estimulación Eléctrica , Embrión de Mamíferos , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/genética , Proteínas Luminiscentes/genética , Masculino , Ratones , N-Metilaspartato/farmacología , Neuronas/efectos de los fármacos , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/genética , Ratas , Ratas Wistar , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Transfección/métodos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
Dominant mutations in the amyloid precursor protein (APP) gene are associated with rare cases of familial Alzheimer's disease; however, the normal functions of APP and related proteins remain unclear. The nematode Caenorhabditis elegans has a single APP-related gene, apl-1, that is expressed in multiple tissues. Loss of apl-1 disrupts several developmental processes, including molting and morphogenesis, and results in larval lethality. The apl-1 lethality can be rescued by neuronal expression of the extracellular domain of APL-1. These data highlight the importance of the extracellular domain of an APP family member and suggest that APL-1 acts noncell-autonomously during development. Overexpression of APL-1 also causes several defects, including a high level of larval lethality. Decreased activity of sel-12, a C. elegans homologue of the human gamma-secretase component presenilin 1, partially rescues the lethality associated with APL-1 overexpression, suggesting that SEL-12 activity regulates APL-1 activity either directly or indirectly.