Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558694
Title: An examination of the physiological role of the schizophrenia susceptibility gene DTNBP1
Author: Malins, Richard
Awarding Body: Oxford University
Current Institution: University of Oxford
Date of Award: 2011
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Abstract:
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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.558694  DOI: Not available
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