| Popis: |
The synaptic hypothesis of schizophrenia proposes that a fundamental dysfunction in synaptic transmission accounts for the complex and heterogeneous pathology of schizophrenia. As neurotransmission subsequently shapes the development and organisation of synaptic contacts, a transmission deficit could lead to abnormal neuronal network development and diminished plasticity along with the emergence of clinical symptoms. Recent molecular genetics studies have identified Dysbindin-l (DTNBP 1) as a schizophrenia susceptibility gene; DTNBP 1 is expressed in the hippocampus and prefrontal cortex and is thought to play a part in glutamate neurotransmission. However, an exact role of DTNBPl in the pathophysiology of schizophrenia has yet to be identified. As described here, alterations in the expression level of DTNBP 1 cause a severe and selective hypofunction of the N-methyl D-aspartate (NMDA) subclass of ionotropic glutamate receptors, as well as blocking the induction of long-term potentiation (LTP), thought to be, the molecular substrate of learning and memory. DTNBPl " overexpression promotes a rapid re-internalisation of NMDARs through clathrin- dependent endocytosis, leading to a paucity of receptors at the cell surface. Blocking endocytosis can restore normal NMDAR function-and surface expression. Altered glutamate neurotransmission and NMDA receptor hypofunction have long been posited to play a central role in the synaptic abnormalities of schizophrenia. The data presented here suggest that altered expression of DTNBPl impacts NMDA receptor trafficking and creates a synaptic pathology reminiscent of schizophrenia. This study also suggests regulation of NMDA receptor trafficking rather than direct modulation of NMDA receptor function as a potential therapeutic target for the treatment of schizophrenia. |
