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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.
References:
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
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