I recommend the Primary Papers

Over the past few years, specific disruptions in the function of presynaptic, glutamate-releasing terminals in the cortex of animals with genetic insufficiency in dysbindin have been hypothesized and found in mammalian preparations (Talbot et al., 2004; Numakawa et al., 2004; Chen et al., 2008; Jentsch et al., 2009). Setting out to discover genes involved in presynaptic function in Drosophila, Dickman and Davis provide powerful convergent evidence supporting this biological role for the dysbindin protein. The seemingly similar functions for this protein in mammalian cortical synapses and at the invertebrate neuromuscular junction is an exciting finding, though one that should not be interpreted without caution.

Overall, the presynaptic defects that result from loss of dysbindin expression could be the basis of failures of sustained network activity in cortical regions that subserve representational knowledge and working memory-like processes. On the other hand, increasing attention is being focused on the consequences of dysbindin loss for components of the post-synaptic zone. Impaired receptor trafficking and alterations in cell excitability have been reported in pyramidal cells and fast-spiking cells (Ji et al., 2009; Jentsch et al., 2009).

Much remains unknown. What are the molecular mechanisms by which alterations in receptor trafficking are altered in post-synaptic targets? Are these cell autonomous effects or changes secondary to particular disturbances in network function caused by presynaptic dysfunction? Are pyramidal cells and/or particular subsets of interneurons more impacted?

Moreover, if there are disturbances in expression of particular isoforms of dysbindin, are these effects due to genetic variation within the DTNBP1 locus, or are these genomic phenotypes a result of transcriptional or translational influences on DTNBP1 expression?

It is clear that the biology of this gene and its associated protein is of great interest. Increasingly sophisticated tools that allow cell-type-specific regulation and/or modulation of expression in an isoform specific manner are required to help elucidate the answers to these questions.

References:

Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, Hahn CG, Siegel SJ, Trojanowski JQ, Gur RE, Blake DJ, Arnold SE. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest . 2004 May 1 ; 113(9):1353-63. Abstract

Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, Ozaki N, Taguchi T, Tatsumi M, Kamijima K, Straub RE, Weinberger DR, Kunugi H, Hashimoto R. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet . 2004 Nov 1 ; 13(21):2699-708. Abstract

Chen XW, Feng YQ, Hao CJ, Guo XL, He X, Zhou ZY, Guo N, Huang HP, Xiong W, Zheng H, Zuo PL, Zhang CX, Li W, Zhou Z. DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. J Cell Biol . 2008 Jun 2 ; 181(5):791-801. Abstract

Dickman DK, Davis GW. The Schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science 2009 November 20; 326: 1127-1130.

Jentsch et al. Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacol. 2009; 34(12):2601-8. Abstract

Ji Y, Yang F, Papaleo F, Wang H-X, Gao W-J, Weinberger DR, Lu B. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. PNAS 2009 November 3. Abstract

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