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Carlson GC, Talbot K, Halene TB, Gandal MJ, Kazi HA, Schlosser L, Phung QH, Gur RE, Arnold SE, Siegel SJ. Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia. Proc Natl Acad Sci U S A. 2011 Oct 25 ; 108(43):E962-70. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Antonieta Lavin
Submitted 9 November 2011
Posted 10 November 2011
  I recommend the Primary Papers

The findings by Shao and collaborators are very exciting, and since their preparation allows for very sophisticated genetic manipulations, the possibility of isolating and reversing the effects of lack of dysbindin in neurons and glia provide important insights into the function of this extremely interesting protein. One result of the study that is relevant for future therapeutic endeavors is the finding that adding glycine to the diet of mutant flies improved memory. We have shown (Glen et al., 2009) that adding glycine to the perfusion buffer of a hippocampal slice preparation from dysbindin-null mice (C57) restored the decreased LTP levels in the null mice without affecting LTP in the WT genotype. Moreover, Shao and colleagues' finding stresses the important role of dysbindin in regulating NMDA receptors. We have already demonstrated that NMDA currents are decreased in dysbindin-null mice, as is expression of the obligatory NMDA receptor subunit (NR1). Furthermore, the degree of NR1 expression directly correlates with performance on a spatial working memory task, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression (Karlsgodt et al., 2011). However, it will be necessary to investigate the molecular mechanisms mediating changes in glutamate and dopamine after deletion of dysbindin.

Recent experiments by us (Sagu et al.), to be presented this year at the Annual Meeting of the Society for Neuroscience, show that loss of dysbindin produces small, synaptic, releasable pools; elicits a deficit in synaptic vesicle dynamics; and decreases levels of proteins involved in priming of synaptic vesicles and in vesicle dynamics. Moreover, dysbindin-null mice exhibit a lower concentration of Ca++.

However, much remains to be known, as the study of this interesting gene and its related proteins is a deserving research field for understanding schizophrenia and bipolar disorder.

References:

Glen B., New, N.N. Mulholland, P., Chandler, J and Lavin, A. (2009) Dysbindin-1 mutation impairs synaptic plasticity in hippocampus: A successful recovery strategy through modulation of NMDA receptor function. Society for Neuroscience.

Karlsgodt KH, Robleto K, Trantham-Davidson H, Jairl C, Cannon TD, Lavin A, Jentsch JD. Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry . 2011 Jan 1 ; 69(1):28-34. Abstract

Sagu S. and Lavin A. (2011) Presynaptic effects of dysbindin mutation: Are SNARE complexes involved?. Society for Neuroscience, Washington, DC (386.07).

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