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Dopamine Signals Stall Dendritic Spine Formation in Young Mice

October 15, 2013. Overactive dopamine receptors during brain development can leave a lasting impression on the brain, according to a study published October 13 in Nature Neuroscience. Researchers led by Zheng Li at the National Institute of Mental Health in Bethesda, Maryland, found that activity through D2 dopamine receptors (D2Rs) in the hippocampus of mice reduced dendritic spine numbers, but only when the signaling was boosted during a stage of mouse development loosely equivalent to adolescence in humans. This overactive D2R signaling in adolescence resulted in connectivity disruptions and a working memory deficit in adulthood.

The findings point to a link between two features of schizophrenia: the overactive D2R signaling hypothesized to precede and drive psychosis (see SRF hypothesis paper) and the reduction in dendritic spines found in postmortem brain samples from people with schizophrenia (Glausier et al., 2013; see SRF related news story). Dendritic spines are the receiving end of excitatory synapses, and changes to them could significantly alter information flow through the brain. Brain imaging continues to uncover connectivity changes in schizophrenia (see SRF related news story) that may be related to cognition (see SRF related news story).

The findings also highlight adolescence as a special time in brain development. Though early brain development has captured the bulk of research interest, the teenage brain is starting to be recognized for the important maturational processes underway at that time (see SRF conference report): When derailed, these might heighten risk for schizophrenia (see SRF related news story). The adolescent brain also seems more plastic than the adult brain: In a rat model of schizophrenia, adolescent rats benefit from cognitive training that was not helpful to adult rats (see SRF news related story). The new study, too, points to enhanced plasticity in adolescence, which may guide future treatment strategies.

Sculpting spines
Using several approaches, first author Jie-Min Jia and colleagues found that D2R activity influenced dendritic spine numbers in mice at postnatal day 21—an age that might be considered comparable to early adolescence in humans—just after weaning, but before sexual maturity. Excitatory synapses are actively being made at this time. The researchers injected these mice with D2R agonists (quinpirole or bromocriptine), waited 24 hours, then made hippocampal slices from their brains and labeled CA1 neurons. This revealed a slight decrease in spine density compared to mice injected with vehicle. In contrast, injection with the D2R blocker eticlopride increased spine density relative to controls. Likewise, overexpressing D2Rs with constructs delivered to the hippocampus via a lentiviral vector resulted in lower spine density, whereas knocking down D2Rs increased spine density.

D2R activation seemed to stall the transition from immature to mature dendritic spines. Spines begin as a stringy filopodium, then fatten into stubby spines before constricting at the stalk and bloating at the tip to take on a mature mushroom shape or a thinner shape marked by a small head and a long neck. In hippocampal neurons cultured for 14 days, D2R agonists reduced the density of mushroom and thin spines, increased filopodium density, but produced no change in stubby spines. Time-lapse imaging during one hour of quinpirole treatment revealed active spine remodeling in which fewer mature spines successfully took root compared to controls.

Inside the neurons, the researchers identified some of the molecular middlepersons between D2R activation and spine reduction. The cAMP pathway downstream of D2Rs was involved, as were GluN2Bs, a subunit of the NMDA type of glutamate receptor (NMDAR) that characterizes immature synapses.

Age dependence
The researchers next looked at mice that overexpressed D2Rs. Called “sandy” mice, these animals carry a natural deletion in dysbindin, a gene linked to schizophrenia that is involved in trafficking D2Rs to the cell membrane (see SRF related news story; SRF news story). Consistent with the previous experiments, the sandy mice showed a reduction in spine density relative to wild-type littermates—either in slices made from P21 mice or in hippocampal cultures. This reduction could be counteracted by knockdown of D2Rs via siRNA transfection or by boosting cAMP, suggesting the same connection with D2R signaling. D2Rs were central: The selective D2R blocker loxapine normalized spine density in sandy mice, whereas the less selective clozapine did not.

But the spine reduction occurred only during the time window of mouse "early adolescence": while sandy mice showed reduced spine density in the hippocampus relative to wild-type mice between three and six weeks of age, at two, eight, and 12 weeks their spine density was normal. Even knocking down D2Rs in adult sandy mice via lentivirus vector could not force a change in dendritic spine density, as though the D2R-spine mechanism becomes uncoupled in adulthood. Similar results were found in wild-type mice, and further experiments indicated that the critical time window hinged on GluN2Bs: Mature neurons could be tricked into responding to quinpirole with a decrease in dendritic spines when GluN2Bs were overexpressed, as is found in young synapses.

Connection to working memory?
Although spine density returns to normal in adults, the researchers found that the period of D2R overactivation at P21 had lasting effects on connectivity between the entorhinal cortex and its hippocampal target. Retrograde tracers injected into the CA1 layer of the hippocampus filled neurons in both the medial and lateral parts of the entorhinal cortex in adult wild-type mice, but this connectivity was shifted toward the lateral part in adult sandy mice. Treating them with a D2R blocker at P21—but not in adulthood—prevented this shift, and similar results were obtained in wild-type mice treated with quinpirole.

Overactive dopamine signaling in early adolescence may have also spurred deficits in spatial working memory, which relies on connectivity between hippocampus and entorhinal cortex. When placed in a Y maze, mice will typically enter each of the three arms consecutively, which reflects some memory for where they have recently been. Adult sandy mice alternated between the arms a bit less than wild-type mice did; similarly, wild-type mice that received a pharmacological boost to D2R activity at P21 alternated less than sandy mice treated with D2R blockers at the same age did. Finally, sandy mice treated with D2R blockers as adults still showed deficient alternation, which suggests that the window for engaging the dopamine-dendritic spine mechanism had closed.

Although future experiments will have to probe more thoroughly the cognitive effects of such dendritic spine changes, the findings point to early adolescence as a special time for brain plasticity. Schizophrenia does not usually announce itself until late adolescence or early adulthood, but studies of the prodrome may increasingly identify signs of derailed brain maturation. If these coincide with times of enhanced adolescent plasticity, then this may provide a special opportunity for treatment, or even prevention.—Michele Solis.

Reference:
Jia JM, Zhao J, Hu Z, Lindberg D, Li Z. Age-dependent regulation of synaptic connections by dopamine D2 receptors. Nature Neuroscience. 2013 Oct 13. Abstract

Comments on Related News


Related News: Studies Suggest Potential Roles for Dysbindin in Schizophrenia

Comment by:  Philip Seeman (Disclosure)
Submitted 29 November 2007
Posted 29 November 2007
  I recommend the Primary Papers

The publication by Iizuka and colleagues is an important advance toward unraveling the basic biology of psychosis in general, and schizophrenia in particular. This is because they have found that a pathway known to be genetically associated with schizophrenia can alter the surface expression of dopamine D2 receptors. D2 continues to be the main target for all antipsychotic drugs (including aripiprazole and even the new Lilly glutamate agonists that have a potent affinity for D2High receptors).

In fact, the authors of this excellent study may do well to go one step further by testing whether the downregulation of dysbindin actually increases the proportion of D2 receptors that are in the high-affinity state, namely D2High. This is because all schizophrenia animal models markedly increase the proportion of D2High receptors by 100 to 900 percent (Seeman et al., 2005; Seeman et al., 2006). This generalization holds for animal models based on brain lesions, sensitization by amphetamine, phencyclidine, cocaine, caffeine or corticosterone, birth injury, social isolation, and more than 15 gene deletions in pathways for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. Although the proportion of D2High receptors invariably increases markedly, the total number of D2 receptors is generally unchanged, slightly reduced, or modestly elevated.

This publication for the first time bridges the hitherto wide gap between genetics and the antipsychotic targeting of the main cause of psychotic signs and symptoms, which is excessive D2 activity, presumably that of D2High, the functional component of D2.

References:

Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8. Epub 2005 Feb 16. Abstract

Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder JC, Quirion R, Boksa P, Srivastava LK, Yanai K, Weinshenker D, Sumiyoshi T. Psychosis pathways converge via D2high dopamine receptors. Synapse. 2006 Sep 15;60(4):319-46. Review. Abstract

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Related News: Studies Suggest Potential Roles for Dysbindin in Schizophrenia

Comment by:  Christoph Kellendonk
Submitted 4 December 2007
Posted 4 December 2007

The study by Iizuka and colleagues is indeed very interesting. It suggests that one of the most promising risk genes for schizophrenia, the dysbindin gene, may functionally interact with dopamine D2 receptors. The D2 receptor itself is an old candidate in the study of schizophrenia, mostly because until very recently all antipsychotic medication had been directed against D2 receptors. But in addition, PET imaging studies have shown that the density and occupancy of D2 receptors is increased in drug-free and drug-naïve patients with schizophrenia.

How could this increase arise? In a subpopulation of patients it may be due to a polymorphism in the D2 receptor gene, the C957T polymorphism. The C-allele increases mRNA stability and has been found to be associated with schizophrenia, though obviously not all patients carry the C-allele. Iizuka and colleagues found an independent way in which the genetic risk factor dysbindin may upregulate D2 receptor signaling. Because dysbindin is downregulated in the brains of patients with schizophrenia, they used siRNA technology to study the molecular consequences of decreased dysbindin levels in cell culture.

They found that downregulation of dysbindin increases D2 receptor density in the outer cell membrane, suppresses dopamine-induced D2 receptor internalization, and increases D2 receptor signaling. The study is very promising but requires further confirmation.

How specific are the observed effects for D2 receptors? Because dysbindin is involved in both membrane trafficking and degradation of synaptic vesicles, knocking down dysbindin in growing cells may affect many physiological processes, one of them being D2 receptor signaling. Does quinpirole treatment differentially affect GTPgS incorporation in siRNA and control cells? This would be a more immediate way of looking at D2 signaling than measuring CREB phosphorylation. And, of course, the most important question is, What will happen in vivo? Maybe the sandy mouse, which carries a deletion in the dysbindin gene, could be of help here. Using these mice for a similar line of experiments may answer this question.

Iizuka and colleagues found an exciting new functional interaction between two major molecules involved in schizophrenia. I believe that these are the kind of interactions we have to look for if we want to understand complex genetic disorders such as schizophrenia.

View all comments by Christoph Kellendonk

Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Vince Calhoun
Submitted 27 January 2009
Posted 27 January 2009

In this work the authors test for differences in the default mode network between healthy controls, patients with schizophrenia, and first degree relatives of the patients. They look at both the degree to which the default mode is modulated by a working memory task and also examine the strength of the functional connectivity. The controls are found to show the most default mode signal decrease during a task, with relatives and patients showing much less. The controls, relatives, and patients show increasing amounts of functional connectivity within the default mode regions. In addition, signal in some of the regions correlated with positive symptoms. The findings in the chronic patients and controls are consistent with our previous work in Garrity et al., 2007, which also showed significantly more functional connectivity in the default mode of schizophrenia patients and significant correlations in certain regions of the default mode with positive symptoms, and in both cases the regions we identified are similar to those shown in the Whitfield-Gabrieli paper. Our work in Kim et al., 2009, was a large multisite study showing significantly fewer default mode signal decreases for the auditory oddball task in chronic schizophrenia patients, again consistent with the Whitfield-Gabrieli paper, but in a different task.

The most interesting contribution of the Whitfield-Gabrieli paper is their inclusion of a first-degree relative group. They found that the first-degree relatives are “in between” the healthy controls and the chronic patients in terms of both the degree to which they modulate the default mode, as well as in their degree of functional connectivity. This has interesting implications in terms of the genetic aspects of the illness and suggests that the default mode may be a potential schizophrenia endophenotype. It will be interesting in future studies to examine both the heritability of the default mode patterns and their genetic underpinnings.

View all comments by Vince Calhoun

Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Edith Pomarol-Clotet
Submitted 28 January 2009
Posted 28 January 2009

The Default Mode Network and Schizophrenia
For a long time functional imaging research has focused on brain activations. However, since 2001 it has been appreciated that there is also a network of brain regions—which includes particularly two midline regions, the medial prefrontal cortex and the posterior cingulate cortex/precuneous—which deactivates during performance of a wide range of cognitive tasks. Why some brain regions should be active at rest but deactivate when tasks have to be performed is unclear, but there is intense speculation that this network is involved in functions such as self-reflection, self-monitoring, and the maintenance of one’s sense of self.

Could the default mode network be implicated in neuropsychiatric disease states? There is evidence that this is the case in autism, and a handful of studies have been also carried out in schizophrenia. Now, Whitfield-Gabrieli and colleagues report that 13 schizophrenic patients in the early phase of illness showed a failure to deactivate the anterior medial prefrontal node of the default mode network when they performed a working memory task. They also find that failure to deactivate is seen to a lesser but still significant extent in unaffected first-degree relatives of the schizophrenic patients, and that the degree of failure to deactivate is associated with both the severity of positive and negative symptoms in the patients.

Importantly, the findings of Whitfield-Gabrieli and colleagues are closely similar to those of another recent study by our group (Pomarol-Clotet et al., 2008), which found failure to deactivate in the medial prefrontal cortex node of the default mode network in 32 chronic schizophrenic patients. This is a striking convergence in the field of functional imaging studies of schizophrenia, which has previously been marked by diverse and often conflicting findings. Additionally, in both studies the magnitude of the difference between patients and controls was large and visually striking. These findings suggest that we may be dealing with an important abnormality which could be close to the disease process in schizophrenia.

If so, what does dysfunction in the default mode network mean? On the one hand, failure to deactivate part of a network whose activity normally decreases when attention has to be turned to performance of external tasks might be expected to interfere with normal cognitive operations. Consistent with this, cognitive impairment is nowadays accepted as being an important, or even a “core” feature of schizophrenia. Perhaps more importantly, could it be that default mode network dysfunction can help us understand the symptoms of schizophrenia? As Whitfield-Gabrieli and colleagues note, if the default mode network is involved in self-reflection, self-monitoring, and maintenance of one’s sense of self, then failure of deactivation might lead to an exaggerated focus on one’s own thoughts and feelings, excessive self-reference, and/or a breakdown in the boundary between the inner self and the external world. The default mode network may thus have the potential to account for two major realms of clinical abnormality in schizophrenia—its symptoms and the cognitive impairment that is frequently associated with them.

View all comments by Edith Pomarol-Clotet

Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Samantha BroydEdmund Sonuga-Barke
Submitted 4 February 2009
Posted 4 February 2009

The surge in scientific interest in patterns of connectivity and activation of resting-state brain function and the default-mode network has recently extended to default-mode brain dysfunction in mental disorders (for a review, please see Broyd et al., 2008). Whitfield-Gabrieli et al. examine resting-state and (working-memory) task-related brain activity in 13 patients with early-phase schizophrenia, 13 unaffected first-degree relatives, and 13 healthy control participants. These authors report hyperconnectivity in the default-mode network in patients and relatives during rest, and note that this enhanced connectivity was correlated with psychopathology. Further, patients and relatives exhibited reduced task-related suppression (hyperactivation) of the medial prefrontal region of the default-mode network relative to the control group, even after controlling for task performance.

The findings from the Whitfield-Gabrieli paper are in accordance with those from a number of other research groups investigating possible default-mode network dysfunction in schizophrenia. For example, in a similar working memory task Pomarol-Clotet and colleagues (2008) have also shown reduced task-related suppression of medial frontal nodes of the default-mode network in 32 patients with chronic schizophrenia. However, the findings are at odds with research reporting widespread reductions in functional connectivity in the resting brain of this clinical group (e.g., Bluhm et al., 2007; Liang et al., 2006). As noted by Whitfield-Gabrieli et al., increased connectivity and reduced task-related suppression of default-mode activity may redirect attentional focus from task-related events to introspective and self-referential thought processes. The reduced anti-correlation between the task-positive and default-mode network in patients further supports and helps biologically ground suggestions of the possibility of an overzealous focus on internal thought. Perhaps even more interestingly, the study by Whitfield-Gabrieli and colleagues suggests that aberrant patterns of activation and connectivity in the default-mode network, and in particular the medial frontal region of this network, may be associated with genetic risk for schizophrenia. Although there are some inconsistencies in the literature regarding the role of the default-mode network in schizophrenia, the work of Whitfield-Gabrieli and others suggests that this network may well contribute to the pathophysiology of this disorder and is relevant to contemporary models of schizophrenia. Indeed, the recent flurry in empirical research investigating the clinical relevance of this network to mental disorder has highlighted a number of possible putative mechanisms that might link the default-mode network to disorder. Firstly, effective transitioning from the resting-state to task-related activity appears to be particularly vulnerable to dysfunction in mental disorders and may be characterized by deficits in attentional control. Sonuga-Barke and Castellanos (2007) have suggested that interference arising from a reduction in the task-related deactivation of the default-mode network may underlie the disruption of attentional control. The default-mode interference hypothesis proposes that spontaneous low-frequency activity in the default-mode network, normally attenuated during goal-directed tasks, can intrude on task-specific activity and create cyclical lapses in attention resulting in increased variability and a decline in task performance (Sonuga-Barke and Castellanos, 2007). Sonuga-Barke and Castellanos (2007) suggest that the efficacious transition from rest to task and the maintenance of task-specific activity may be moderated by trait factors such as disorder. Secondly, the degree of functional connectivity in the default-mode network may highlight problems of reduced connectivity, or excess functional connectivity (e.g., schizophrenia), which suggests a zealous focus on self-referential processing and introspective thought. Thirdly, the strength of the anti-correlation between the default-mode and task-positive networks may also indicate a clinical susceptibility to introspective or extrospective orienting. Finally, future research should continue to examine the etiology of the default-mode network in schizophrenia.

References:

Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., Théberge, J., Schaefer, B., & Williamson, P. (2007). Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: Anomalies in the default network. Schizophrenia Bulletin, 33, 1004-1012. Abstract

Broyd, S.J., Demanuele, D., Debener, S., Helps, S.K., James, C.J., & Sonuga-Barke, E.J.S. (in press). Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2008 Sep 9. Abstract

Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., and Hao, Y. (2006). Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. NeuroReport, 17, 209-213. Abstract

Pomarol-Clotet, E., Salvador, R., Sarro, S., Gomar, J., Vila, F., Martinez, A., Guerrero, A.,Ortiz-Gil, J., Sans-Sansa, B., Capdevila, A., Cebemanos, J.M., McKenna, P.J., 2008. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default-mode network? Psychological Medicine, 38, 1185–1193. Abstract

Sonuga-Barke, E.J.S., Castellanos, F.X., 2007. Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neuroscience Biobehavioural Reviews, 31, 977–986. Abstract

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Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Yuan ZhouTianzi JiangZhening Liu
Submitted 18 February 2009
Posted 22 February 2009
  I recommend the Primary Papers

The consistent findings on default-mode network in human brain have attracted the researcher’s attention to the task-independent activity. The component regions of the default-mode network, especially medial prefrontal cortex and posterior cingulate cortex/precuneus, are related to self-reflective activities and attention. Both of these functions are observed to be impaired in schizophrenia. And thus the default-mode network has also attracted more and more attention in the schizophrenia research community. The study of Whitfield-Gabrieli et al. shows a further step along this research streamline.

The authors found hyperactivity (reduced task suppression) and hyperconnectivity of the default network in schizophrenia, and found that hyperactivity and hyperconnectivity of the default network are associated with poor work memory performance and greater psychopathology in schizophrenia. And they found less anticorrelation between the medial prefrontal cortex and the right dorsolateral prefrontal cortex, a region showing increased task-related activity in schizophrenia, whether during rest or task. Furthermore, the hyperactivity in medial prefrontal cortex is negatively related to the hyperconnectivity of the default network in schizophrenia.

There are two main contributions in this work. First, they found significant correlation between the abnormalities in the default mode network and impaired cognitive performance and psychopathology in schizophrenia. Thus they propose a new explanation for the impaired working memory and attention in schizophrenia, and propose a possibility that schizophrenic symptoms, such as delusions and hallucinations, may be due to the blurred boundary between internal thoughts and external perceptions. Secondly, they recruited the first-degree relatives of these patients in this study, and found that these healthy relatives showed abnormalities in the default network similar to that of patients but to a lesser extent. This is the first study investigating the default mode network of relatives of individuals with schizophrenia. This finding indicates that the dysfunction in the default mode network is associated with genetic risk for schizophrenia.

The findings in schizophrenia are consistent with our previous work (Zhou et al., 2007), in which we also found hyperconnectivity of the default mode network during rest. Considering the differences in ethnicity of participants (Chinese in our study) and methodology, the consistency in the hyperconnectivity of the default mode network in schizophrenia is exciting, which supports the possibility that abnormality in the default-mode network may be a potential imaging biomarker to assist diagnosis of schizophrenia. However, this needs to be validated in future studies with a large sample size, due to other contradictory findings, for example, the reduced resting-state functional connectivities associated with the posterior cingulate cortex in chronic, medicated schizophrenic patients (Bluhm et al., 2007). In addition, further studies should focus on default-mode function in different clinical subtypes, as schizophrenia is a complicated disorder. Finally, it should be noticed that the hyperconnectivity of the default-mode network is not exclusively contradictory with hyperconnectivity in other regions, as we previously found (Liang et al., 2006). It is possible that hyperconnectivity and hyperconnectivity coexist in the brains of individuals with schizophrenia and together lead to the complicated symptoms and cognitive deficits.

References:

Bluhm, R. L., Miller, J., Lanius, R. A., Osuch, E. A., Boksman, K., Neufeld, R. W., et al., 2007. Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophr Bull 33, 1004-1012. Abstract

Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., et al., 2006. Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. Neuroreport 17, 209-213. Abstract

Whitfield-Gabrieli, S., Thermenos, H. W., Milanovic, S., Tsuang, M. T., Faraone, S. V., McCarley, R. W., et al., 2009. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A 106, 1279-1284. Abstract

Zhou, Y., Liang, M., Tian, L., Wang, K., Hao, Y., Liu, H., et al., 2007. Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophr Res 97, 194-205. Abstract

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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.

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

View all comments by J David Jentsch

Related News: Is Early Cognitive Training Key to Minimizing Schizophrenia Impact?

Comment by:  Til Wykes
Submitted 24 August 2012
Posted 24 August 2012

The notion that cognitive remediation is effective in producing cognitive and functional gains in established schizophrenia (Wykes et al., 2011), and produces other gains such as changes identified in brain imaging (e.g., Wykes et al., 2002) is unsurprising. But the paper on remediation in adolescent rats by Lee and colleagues provides results that the authors do consider surprising, and could lead to further extensions of cognitive remediation to those who are "at risk" for disorders such as schizophrenia. This is because of the procognitive effects of providing training in youthful rats.

Procognitive effects of experience-based training are not, however, surprising. The authors quote research showing that there are functional changes with training—the one that springs to my mind is London taxi drivers whose hippocampi are larger following their "training" for The Knowledge—an all-roads-in-London test. So why are the authors surprised? Perhaps it is because the results may have further implications for treatment and prevention, but only if followed up in those who are “at risk,” a notion that has produced much heat and not much light in the annals of SRF. We have been optimistic about the possibility of change in prodromal patients using cognitive behavioral therapy, but that hope has not yet been justified in the current research. It may be that this form of experience-based learning is of greater help in the prodromal group than the traditional cognitive behavioral therapies. It may also be that we need to begin our interventions in school by identifying those who are cognitively at risk for many different future problems, not just schizophrenia.

The results also suggest that even when there is a known lesion, it is possible to normalize behavior as well as produce some correlated neuronal change. This is exciting, as it opens up the possibility of finding cures, if not for the whole disorder at least for some of the problems or symptoms of schizophrenia. All this can be produced by a non-pharmacological intervention. This is something that will surely excite the providers of healthcare, as the cost-benefit would be very high if the future health costs for these patients were reduced through such means.

References:

Wykes T, Brammer M, Mellers J, Bray P, Reeder C, Williams C, Corner J. Effects on the brain of a psychological treatment: cognitive remediation therapy: functional magnetic resonance imaging in schizophrenia. Br J Psychiatry. 2002 Aug;181:144-52. Abstract

Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry . 2011 May ; 168(5):472-85. Abstract

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Related News: Is Early Cognitive Training Key to Minimizing Schizophrenia Impact?

Comment by:  Angus MacDonald, SRF Advisor
Submitted 24 August 2012
Posted 24 August 2012

In their new Neuron article, Lee and colleagues from Andre Fenton’s group at NYU report that spatial cognitive control deficits in a rat model of schizophrenia can be prevented through a ratish analogue of cognitive remediation therapy during adolescence. The importance of early intervention has been one of the hottest debates in applied schizophrenia research; the current findings suggest a basic mechanism in support of such efforts.

What is remarkable about the Fenton study is how small a training “dosage” was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the rats’ capacity to use spatial cognitive control eight to nine weeks after birth.

Rats were sacrificed at the end of the experiment, allowing the researchers to examine the extent to which the initial lesion had affected brain development. The initial lesions dramatically altered hippocampal development. Despite this, lesioned rats who received training did not show any observable difference in brain morphology in adulthood compared to lesioned rats who did not receive training. That is to say, the integrity of the hippocampus measured grossly did not predetermine that rats would perform poorly on the spatial cognitive control task—if they received training. However, subsequent analysis demonstrated that phase synchronization between the hippocampus and prefrontal cortex (which rats possess, albeit not in extremis) was compromised in the lesioned rats who did not receive training, but was recovered in those that did receive training.

Thus, the data suggest that fundamentally important circuitry can be guided through training that is relevant for later cognitive functioning.

What is absent is evidence for the specialness of adolescent intervention. This seems to be assumed from previous work rather than the result of comparisons of implementing the intervention at different ages.

It’s also interesting to note that hippocampal lesion models are generally evaluated using memory-related tasks. Fenton’s task presents something of a hybrid. The spatial cognitive control paradigm used is appropriately adapted to the species in question, but in the abstract it has features similar to that of the Stroop task. In Fenton’s active place avoidance task, there is a dominant channel for responding on which the rat is over-trained, like the Stroop task's word reading component on which most people reading this text have been over-training. There is also a subordinate channel for responding, with which the rat is familiarized, something like color naming on the Stroop task. However, a key aspect of the manipulation is the inability to learn a new zone to avoid, which may be more akin to perseveration than to Stroop performance. Rotation of shock zone to a new location is described as task transference, but since the original learning was a source of interference (and needed to be inhibited) in the subsequent task, I’m not sure I agree with this description.

This work will be warmly received by a large number of advocates who are pushing for interventions earlier in the risk period. One advantage the authors had compared to those in the clinical schizophrenia field is that they knew which of their rats were strongly exposed and were therefore at the highest risk. While our screening tools have been honed over the past decade, they still have a high false-positive rate. One can take some solace, though, that cognitive remediation is unlikely to have extensive negative side effects. Except, perhaps, boredom.

View all comments by Angus MacDonald

Related News: Is Early Cognitive Training Key to Minimizing Schizophrenia Impact?

Comment by:  Patrick McGorry
Submitted 27 August 2012
Posted 27 August 2012

I am always a little skeptical of animal models of psychosis or schizophrenia, which are pretty high-order disturbances and seem very specific to humans. If this model has some validity, the preventive therapy in humans would be more akin to cognitive remediation therapy rather than cognitive therapy per se, which has more CBT links or connotations.

View all comments by Patrick McGorry

Related News: Is Early Cognitive Training Key to Minimizing Schizophrenia Impact?

Comment by:  Barbara K. Lipska
Submitted 27 August 2012
Posted 27 August 2012

Lee et al. report exciting new data in support of the neurodevelopmental hypothesis of schizophrenia and the plausibility of the early intervention that might prevent the emergence of schizophrenia symptoms. Lee and colleagues used a neonatal ventral hippocampal lesion in rats as a model of schizophrenia.

First, using the active place avoidance task with carefully designed control tasks, they showed that the animals with neonatal lesions are cognitively impaired as adults, consistent with the results of the previous studies (see Tseng et al., 2009, for review). Next, they examined whether training of the lesioned animals in adolescence would prevent the emergence of these abnormalities. They exposed the animals to a series of cognitive tests and found that, indeed, the neonatally lesioned rats that acquired additional training as adolescents showed improved cognition in adulthood. Moreover, specific measures of neural function were also improved. The authors recorded local field potentials in the hippocampi and found that the neonatally lesioned animals showed deficits in interhippocampal synchrony, the findings similar to the changes reported in patients with schizophrenia. Adolescent cognitive training normalized interhippocampal synchrony and improved performance on the cognitive tasks in the neonatally hippocampally lesioned rats. Finally, to gain more insight into the mechanisms of these changes, the authors measured cortical thickness and parvalbumin protein content, but these parameters were not informative about the benefits of cognitive training in this animal model of schizophrenia.

The results of this study support the notion that schizophrenia is a neurodevelopmental disorder characterized by discoordinated neural networks, and provide critical evidence for the benefits of early behavioral intervention. Although we still do not fully understand the pathophysiological mechanisms underlying schizophrenia, or the mechanisms responsible for the improvements due to cognitive training, this work certainly offers a potential new therapeutic tool in the form of preemptive cognitive therapy.

References:

Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res . 2009 Dec 7 ; 204(2):295-305. Abstract

View all comments by Barbara K. Lipska