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DISC1: Brief Loss in Prenatal Life Leads to Problems Later On

2 March 2010. If schizophrenia has its roots in early brain development, why does the disease most often appear in adolescence or early adulthood? A new mouse model of DISC1 knockdown may provide some clues to that mystery. In a paper published in the February 25 issue of Neuron, Akira Sawa of Johns Hopkins University in Baltimore, Maryland, Toshitaka Nabeshima of Meijo University in Nagoya, Japan, and colleagues present data showing that a transient prenatal loss of DISC1 protein in the developing cortex in mice is sufficient to cause problems in dopaminergic circuits later on. After puberty, the animals showed both neurotransmitter changes (low dopamine levels) and behavioral changes that have been proposed to model aspects of schizophrenia in animals. The results tie an early developmental snafu to changes in later brain maturation, and provide a method for creating animal models to test the impact of genetic risk factors on development and disease.

The DISC1 (disrupted in schizophrenia-1) gene was first identified in a Scottish family where its truncation by a chromosomal translocation causes schizophrenia and other serious mental disorders. Since then, DISC1 has been found to play important roles in both neuronal development and in brain function in the adult brain (see SRF related news story; SRF related news story; and SfN 2009 meeting coverage). However, just how its loss precipitates schizophrenia is not clear. In previous work from the Sawa group, Atsushi Kamiya showed that a prenatal knockdown of DISC1 in vivo by in utero electroporation of short hairpin RNA into cortical progenitor cells in rats led to abnormal neuronal migration, impaired orientation, and loss of proper dendritic trees (see SRF related news story).

In the new work, Kamiya and co-first author Minae Niwa extend those findings by looking at the long-term structural and behavioral effects of transient loss of DISC1, this time in mice. To do that, they used in vivo electroporation of short hairpin RNAs to target cortical progenitor cells lining the brain ventricles, which mature mainly into pyramidal neurons of the prefrontal cortex. The result was a temporary loss of DISC1 protein in the cells, which lasted until shortly after birth and caused defects in progenitor proliferation, neuronal migration, and changes in arborization, particularly in layer II/III of the cortex. These changes, apparent at two weeks after birth, are consistent with the earlier results of Kamiya and others (Mao et al., 2009). The neurons also showed changes in function, as measured by membrane resistance and capacitance.

The researchers went on to ask if these early changes translated into problems later on. They analyzed four- and eight-week-old mice and found no gross changes in body weight or brain structure, or signs of gliosis in the cortex. However, they did detect a decrease, by nearly 50 percent, of dopamine content in the cortex in the eight-week-old mice, contrary to the usual increase that occurs with maturation. The loss was associated with a decrease in tyrosine hydroxylase positive (dopaminergic) projections in the cortex. Other changes included a reduction in parvalbumin staining in cortical GABAergic interneurons, and electrophysiological alterations in pyramidal neurons. Similar changes have been noted in brain tissue from people with schizophrenia, including reports of decreased arborization and smaller size of interneurons in layers II/III of the cortex, alterations in a subset of parvalbumin-positive interneurons, and reduction in tyrosine hydroxylase staining.

“Taken together, these results suggest that neonatal pyramidal neuron deficits elicited by pre-/perinatal knockdown of DISC1 lead to overall disturbances in circuitry involving dopamine neurons, pyramidal neurons, and interneurons, manifested only after puberty,” the authors write. Of note, the mice did not show changes in dopamine in other brain regions, nor were other neurotransmitters changed in the cortex. No changes were seen in levels of the dopamine receptors D1 or D2.

The mice also displayed behavioral changes proposed to model aspects of schizophrenia. Eight-week-old animals, but not four-week-olds, showed decreased prepulse inhibition, thought to reflect a defect in sensory gating seen in several mental illnesses. Treatment of animals with clozapine normalized dopamine levels and erased the PPI deficit. Other proposed schizophrenia-related phenotypes reported included impaired memory in the novel object recognition test (also improved by clozapine) and hypersensitivity to methamphetamine.

“The present study indicates the sequential link among pre-/perinatal disturbances in a specific genetics susceptibility factor (DISC1), the associated dendritic abnormalities in the neonatal stage, and, in turn, selective phenotypes in adolescence and adulthood,” the authors conclude. The results raise a host of mechanistic questions, from the role of DISC1, to how dendritic abnormalities in layer II/III neurons might lead to decreased dopamine projections, to what might be the trigger that precipitates post-puberty pathophysiology.

Sawa, Nabeshima, and colleagues suggest that the technique of in utero gene transfer opens up the chance to build new animal models by manipulating multiple genes during development and watching how they influence adult behavior. Co-transfection techniques allow for the possibility of testing synergistic or epistatic effects of genes, and the electroporation can be modified to target other neuronal populations. This could be especially useful for adult mental disorders, they write, “including schizophrenia, in which multiple risk factors play etiological roles during neurodevelopment.”

In an accompanying preview, Barbara Thompson and Pat Levitt of the Keck School of Medicine, University of Southern California in Los Angeles, write that the study shows how an early and transient insult can lead to a systemic breakdown and the emergence of a disease state “even in the context of what appears on the surface to be minor ‘cracks’ in brain architecture and molecular status.” The study also raises the “frightening thought that one may never be able to identify signature patterns of psychiatric disease risk, because such early changes may be undetected as a result of the restricted and highly transient nature of the spatial and temporal insults,” they write.—Pat McCaffrey.

References:
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, Lu L, Tomisato S, Jaaro-Peled H, Seshadri S, Hiyama H, Huang B, Kohda K, Noda Y, O’Donnell P, Nakajima K, Sawa A, Nabeshima T. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron. 2010 February 25;65:480-489. Abstract

Thompson BL, Levitt P. Now you see it, now you don’t—Closing in on allostasis and developmental basis of psychiatric disorders. Neuron. 2010 February 25;65:437-439. Abstract

Comments on Related News


Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Anil Malhotra, SRF Advisor
Submitted 21 November 2005
Posted 21 November 2005

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The researchers' elegant set of experiments provides compelling biological evidence that PDE4B interacts with DISC1 and suggests a mechanism mediated by cAMP for DISC1/PDE4B effects on basic molecular processes underlying learning, memory, and perhaps psychosis. It remains possible that PDE4B (and DISC1) are proteins fundamentally involved in cognitive processes, and that the observed relationship to psychotic illnesses represents a final common pathway of neurocognitive impairment. This would be consistent with data from our group (Lencz et al., in press) demonstrating that verbal memory impairment specifically predicts onset of psychosis in at-risk subjects. Similarly, Burdick et al. (2005) found that our DISC1 risk genotypes (Hodgkinson et al., 2004) were associated with impaired verbal working memory. Finally, Callicott et al. (2005) found that a DISC1 risk SNP, Ser704Cys, predicted hippocampal dysfunction, an SNP which we (DeRosse et al., unpublished data) have also found to link with the primary psychotic symptoms (persecutory delusions) manifested by the patient in the Millar et al. study. This body of evidence supports the notion that these proteins play fundamental roles in the key clinical manifestations of schizophrenia.

Kamiya et al. (2005) provide another potential mechanism for these effects, suggesting that a DISC1 mutation may disrupt cerebral cortical development, hinting that studies examining the role of DISC1 genotypes on brain structure and function in the at-risk schizophrenia pediatric patients may be fruitful.

Taken together, these papers add considerable new data suggesting that DISC1 plays a key role in the etiology of schizophrenia, and places DISC1 at the forefront of the rapidly growing body of schizophrenia candidate genes.

References:
Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12):1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102(24): 8627-8632. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in Schizophrenia (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. Abstract

Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry (in press).

View all comments by Anil Malhotra

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Angus Nairn
Submitted 29 December 2005
Posted 31 December 2005
  I recommend the Primary Papers

This study describes an interesting genetic link between PDE4B (phosphodiesterase 4B) and schizophrenia that may be related to a physical interaction with DISC1 (disrupted in schizophrenia 1), another gene associated with the psychiatric disorder. The study is highly suggestive of a role for the PDE4B/DISC1 complex in schizophrenia. However, the mechanistic model suggested by the authors whereby DISC1 sequesters PDE4B in an inactive state seems overly speculative, given the results presented in this paper and in prior studies that have examined the regulation of PDE4B by phosphorylation in the absence of DISC1.

View all comments by Angus Nairn

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers

Related News: DISC1 and SNAP23 Emerge In NMDA Receptor Signaling

Comment by:  Jacqueline Rose
Submitted 2 March 2010
Posted 2 March 2010
  I recommend the Primary Papers

The newly published paper by Katherine Roche and Paul Roche reports SNAP-23 expression in neuron dendrites and examines the possible role of this neuronal SNAP-23 protein. To this point, SNAP-23 has traditionally been discussed in reference to vesicle trafficking in epithelial cells (see Rodriguez-Boulan et al., 2005 for review), so it is of interest to determine the function of SNAP-23 in neurons. Suh et al. report that surface NMDA receptor expression and NMDA-mediated currents are inhibited following SNAP-23 knockdown. Further, SNAP-23 knockdown results in a specific decrease in NR2B subunit insertion; previously, the NR2B subunit has been reported to preferentially localize to recycling endosomes compared to NR2A (Lavezzari et al., 2004). Given these findings, it is reasonable to conclude that SNAP-23 may be involved in maintaining NMDA receptor surface expression possibly by binding to NMDA-specific recycling endosomes.

Interestingly, there is recent evidence that PKC-induced NMDA receptor insertion is mediated by another neuronal SNARE protein; postsynaptic SNAP-25 (Lau et al., 2010). It is possible that activity-induced NMDA receptor trafficking is mediated by SNAP-25, while baseline maintenance of NMDA receptor levels relies on SNAP-23. Other evidence to suggest a strictly regulatory role for SNAP-23 in neuronal NMDA insertion is the finding that activity-dependent receptor insertion from early endosomes has previously been reported to be restricted to AMPA-type glutamate receptors (Park et al., 2004). However, it is possible that activity-induced insertion of AMPA receptors occurs via a distinct endosome pool than NMDA receptors; AMPA and NMDA receptor trafficking has been reported to proceed by distinct vesicle trafficking pathways (Jeyifous et al., 2009).

Although SNAP-23 may not be involved in activity-dependent early endosome receptor trafficking, it is possible that SNAP-23 operates in other pathways linked to activity-induced NMDA receptor trafficking. For instance, SNAP-23 may be the SNARE protein by which lipid raft shuttling of NMDA receptors occurs. SNAP-23 has been found to preferentially associate with lipid rafts over SNAP-25 in PC12 cells (Salaün et al., 2005). As well, NMDA receptors have been found to associate with lipid raft associated proteins flotilin-1 and -2 in neurons (Swanwick et al., 2009). Lipid raft trafficking of NMDA receptors to post-synaptic densities has been reported to follow global ischemia (Besshoh et al., 2005), and the possibility remains that under certain circumstances, NMDA trafficking occurs by lipid raft association to SNAP-23.

Taken together, the discovery of post-synaptic SNARE proteins offers several avenues of research to determine their roles and functions in glutamatergic synapse organization. Further, investigating disruption of synaptic receptor organization presents several possibilities for potential etiologies of disorders linked to compromised glutamate signaling like schizophrenia.

References:

Besshoh, S., Bawa, D., Teves, L., Wallace, M.C. and Gurd, J.W. (2005). Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Journal of Neurochemistry, 93: 186-194. Abstract

Jeyifous, O., Waites, C.L., Specht, C.G., Fujisawa, S., Schubert, M., Lin, E.I., Marshall, J., Aoki, C., de Silva, T., Montgomery, J.M., Garner, C.C. and Green, W.N. (2009). SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature Neuroscience, 12: 1011-1019. Abstract

Lau, C.G., Takayasu, Y., Rodenas-Ruano, A., Paternain, A.V., Lerma, J., Bennet, M.V.L. and Zukin, R.S. (2010). SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. Journal of Neuroscience, 30: 242-254. Abstract

Lavezzari, G., McCallum, J., Dewey, C.M. and Roche, K.W. (2004). Subunit-specific regulation of NMDA receptor endocytosis. Journal of Neuroscience, 24: 6383-6391. Abstract

Park, M., Penick, E.C., Edward, J.G., Kauer, J.A. and Ehlers, M.D. (2004). Recycling endosomes supply AMPA receptors for LTP. Science, 305: 1972-1975. Abstract

Rodriguez-Boulan, E., Kreitzer, G. and Müsch, A. (2005) Organization of vesicular trafficking in epithelia. Nature Reviews: Molecular Cell Biology, 6: 233-247. Abstract

Salaün, C., Gould, G.W. and Chamberlain, L.H. (2005). The SNARE proteins SNAP-25 and SNAP-23 display different affinities for lipid rafts in PC12 cells. Journal of Biological Chemistry, 280: 1236-1240. Abstract

Suh, Y.H., Terashima, A., Petralia, R.S., Wenthold, R.J., Isaac, J.T.R., Roche, K.W. and Roche, P.A. (2010). A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci. 2010 Mar;13(3):338-43. Abstract

Swanwick, C.C., Shapiro, M.E., Chang, Y.Z. and Wenthold, R.J. (2009). NMDA receptors interact with flotillin-1 and -2, lipid raft-associated proteins. FEBS Letters, 583: 1226-1230. Abstract

View all comments by Jacqueline Rose