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Parsing Dysbindin’s Roles in the Brain

8 November 2011. There’s something for everyone’s pet hypothesis of schizophrenia in two recent studies of dysbindin-1 published in the Proceedings of the National Academy of Sciences. A study published online 31 October ties dysbindin-1 in neurons to glutamate signaling in Drosophila, and its action in glia to dopamine effects. Another study published online on 3 October links dysbindin-1 to γ-aminobutyric acid (GABA) signaling in mice.

These links to varied neurotransmitter systems—all implicated in schizophrenia—are part of the allure of dysbindin-1 (see SRF related news story), which seems involved in shuttling proteins to their correct places within cells (Larimore et al., 2011). The gene encoding dysbindin-1, DTNBP1) was first fingered in schizophrenia by a family-based association study (Straub et al., 2002), and has been replicated in some, but not all follow-up studies. It has not been among the hits in GWAS (see SRF related news story), but this has not cooled interest for some researchers (see SRF related news story), who note the dysbindin-1 reductions in postmortem brains in schizophrenia (Tang et al., 2009), a link between dysbindin and synaptic function (Dickman and Davis, 2009), and ties with working memory (Wolf et al., 2011).

The neuron-glia divide
Dysbindin’s role in the brain may depend on location, according to the Drosophila study led by Yi Zhong of Cold Spring Harbor Laboratory in New York. Using genetic tricks useful only in Drosophila, Zhong and his team probed the function of Ddysb, the fruit fly version of dysbindin-1, in neurons and in glia separately. Reducing Ddysb in neurons attenuated glutamate signaling and incurred memory deficits—findings which evoke the underactive glutamate systems hypothesized in schizophrenia (see SRF Hypothesis). In contrast, reducing Ddysb in glia boosted dopamine signaling, which conjures the overactive dopamine state that antipsychotics help suppress (see SRF Hypothesis).

First author Lisha Shao and colleagues studied a mutant fly with a 40 percent reduction in Ddysb expression. These flies had reduced glutamate neurotransmission, enhanced levels of dopamine, impaired olfactory memory for scents paired with an aversive shock, increased locomotor activity, and a reduced preference to mate with flies of the opposite sex. Tissue-specific perturbations found that the glutamate and memory abnormalities resulted from neural reductions in Ddysb, whereas the dopamine, locomotor, and mating abnormalities resulted from glial Ddysb reductions. Further experiments indicated that the elevated dopamine may result from reductions in a protein called Ebony, an enzyme that inactivates dopamine sequestered within glia, which was found in Ddysb mutants.

The researchers could rescue these anomalies in different ways. Engineering the Ddysb mutants to express Ddysb only in their neurons restored glutamate signals to their normal size and normalized olfactory memory; likewise, doing the same in glia lowered dopamine and locomotor activity to wild-type levels, as well as reinstating a mating preference. Glia or neuron-specific expression of human dysbindin, which shares 28 percent amino acid identity with the fruit fly version, also had the same effects. Even acutely adding back Ddysb to neurons or glia in adult flies restored the respective neurotransmitters and behaviors to wild-type levels. This suggests that Ddysb can influence the workings of adult brains, a departure from the neurodevelopmental roles often ascribed to schizophrenia suspects.

Finally, the researchers strengthened the link between disruptions in neurotransmission and altered behavior by finding that acutely boosting glutamate signaling by feeding the mutant flies glycine, an agonist for the NMDA glutamate receptor, improved memory. Conversely, lowering dopamine levels in these mutants with dopamine inhibitors suppressed locomotion and normalized mating preference. These manipulations in wild-type flies had no effect.

Without dysbindin, reduced inhibition
Mice lacking dysbindin-1 also have abnormalities in glutamatergic (Jentsch et al., 2009) and dopaminergic signaling (Ji et al., 2009), but Steven Siegel of University of Pennsylvania in Philadelphia and his team found evidence for inhibitory circuitry alterations in these mice, including deficits in parvalbumin (PV)-containing interneurons. These results are consistent with disruption to inhibition in schizophrenia (see SRF Hypothesis), and the researchers suggest that PV-containing interneurons may constitute a final common disease mechanism for the myriad genetic variants implicated in schizophrenia.

First author Gregory Carlson and colleagues studied “sandy” mice that carry a naturally occurring deletion in the dysbindin-1 gene, leaving them completely without dysbindin-1 (Cox et al., 2009). These mice showed deficits in processing auditory stimuli similar to those found in some patients with schizophrenia: EEG measures of auditory-evoked response adaptations (brain responses to a pair of clicks), prepulse inhibition of startle, and auditory-evoked high-frequency γ-oscillations were all significantly different from those found in wild-type mice.

The researchers suspected PV-containing interneuron abnormalities because these types of neurons mediate γ-oscillations. Looking in the hippocampus, a known contributor to γ-oscillations, they found a reduced density of PV-containing neurons in area CA1, and a decreased amount of PV within these neurons in dysbindin-1 mutants compared to controls. Similar changes were also found in auditory cortex. To see how this decrement in PV-containing interneurons would impact the flow of signals through the circuit, the researchers used voltage-sensitive dye imaging in hippocampal slices. When stimulating the inputs to CA1, they found that the pattern of excitation followed by inhibition was altered in the dysbindin-1 mutants, with much of the inhibition missing.

Whether the reduction in PV-containing interneurons is a direct result of dysbindin-1 loss in these cells or a downstream outcome of the reduced glutamatergic drive associated with dysbindin-1 loss is unclear. But answering this sort of question will be important for understanding how changes to glutamatergic, dopaminergic, and GABAergic signaling interact. Tracing out how reductions to a single protein can cascade into diverse effects across the brain—in neural and non-neural cells alike—will be challenging, but essential for pinpointing any role for dysbindin-1 in schizophrenia.—Michele Solis.

Shao L, Shuai Y, Wang J, Feng S, Lu B, Li Z, Zhao Y, Wang L, Zhong Y. Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila. Proc Natl Acad Sci U S A. 2011 Nov 2. Abstract

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: E962-70. 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.


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).

View all comments by Antonieta Lavin

Comments on Related News

Related News: Dissecting Dysbindin—Mice, Flies Point to Different Roles

Comment by:  J David Jentsch
Submitted 29 November 2009
Posted 30 November 2009
  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.


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

View all comments by J David Jentsch