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December 4, 2011

Neuropsychiatric Disorder Models: Improvement Needed!

Neuropsychiatric disorders such as schizophrenia, depression and bipolar disorder are serious health problems. They have substantial negative affects on a significant subset of the population and are still largely not understood. While the molecular targets of many psychotherapeutic drugs have been successfully reverse engineered, this was done in the 1960's. Despite ongoing efforts to further understand these disorders, little progress has been made since then. This raises the question: why? Two scientists, Eric J Nestler and Steven E Hyman have published an article in the journal Nature Neuroscience seeking to find a solution to this. In their paper, Animal models of neuropsychiatric disorders, they claim that the primary thing holding back research in the field is the difficulty of creating animal models of human psychiatric diagnoses. The authors then seek to contribute to the field by doing an analysis of the currently used models and discussing which ones are most likely to be valid and productive.

It can be very difficult to translate between animal and human thoughts and feelings. Whenever one does so they risk unfairly anthropomorphizing. Since animals are incapable of reporting their feelings researchers need to find round-about ways to determine what is actually going on within an animal's head. The typical methodology then used to study animal behavior and use it as a proxy for mental activity. However for most of the neuropsychiatric disorders that are professionally addressed what constitutes a legitimate disorder is not clearly separated from what constitutes normal variation. Furthermore, the same neuropsychiatric diagnose can be proscribed to two completely different sets of symptoms. This leaves researchers in a position where they must decide for themselves what constitutes a legitimate disorder, how to define it, and the subsequently how it can be represented in behavioral models.

In order to usefully discuss the efficacy of studies relating to these neuropsychiatric disorders, the authors of the article referred to a framework for validating studies with the components construct, face and predictive validity. Construct validity is a measure of how well a model's construction is relevant to a disease. Face validity is a measure of how well a model reiterates the physical and behavioral features of a human disease. Predictive validity is a measure of how well a model's response to treatments compares to patients actual responses to these same treatments.

The article then discusses different things that can be modeled in schizophrenia, depression and bipolar disorder and the validities of potential models. For schizophrenia, it is stated that blunted affect, asocial behavior, diminished motivation and deficits in working memory and/or conscious control of behavior are all symptoms that a behavioral model should seek to measure. The article claims that a good way to creat constructively valid models is to use genetic animal models with highly penetrant human mutations, although it doesn't consider these models to be perfect. It also states that a good (but not sufficient on its own) measure of face validity is a deficit in prepulse inhibition (PPI) of a phenomenon where weak starting stimuli reduce a startle response produced by a following more intense stimulus.

For depression it's stated that neurovegetative symptoms such as abnormalities in sleep, appetite, weight and energy along with psychomotor agitation or retardation are all potential indicators. With the caveat that no abnormality has proven sufficiently robust or consistent enough to validate an animal model the paper claims that chornic social defeat stresses along with chronic mild and chronic unpredictable stress are all capable of inducing states of depression which have some face value. These methodologies are criticized however as potentially setting off an anxiety disorder with similar symptoms instead of modeling depression. The authors suggest that measures of other homeostatic symptoms such as alterations in sleep, circadian rhythms and feeding with attendant metabolic parameters would strengthen claims of depression in animal models.

For bipolar disorder it's stated that the diagnosis comes from periods of mania with or without depression. The article states that transgenic mice have exhibited manic-like behavior when they were programmed to over express glycogen synthase kinase-3beta. These mutants are assesd to meet partial criteria for face validity along with predictive validity. However they failed to meet requirements for contruct validity. The article suggests that mania investigative studies use a broad range of behavioral tests and interpret their data cautiously.

Finally, the article listed some generalized recommendations towards researchers. These recommendations included listing the specific aspects of the illness meant to be model and stating the types of validators applied to the model. The researcher also noted that construct validity is most compelling of the different validities and that it's best to use a broad range of behavioral assays.

It's clear that research into these neuropsychiatric disorders still faces a great deal of hurdles, especially when it comes to assessing bipolar disorder. However, as this paper shows, there is constructive focus being brought to the forefront of this area. With genetic and technological advances combined applied to models with clearly stated rationales and sober discussion of validity significant progress can potentially be made in the field.
Posted by      Michael A. at 11:54 PM MST
  Michael Asnes  says:
Nestler, Eric J., and Steven E. Hyman. "Animal Models of Neuropsychiatric Disorders." Nature Neuroscience 13.10 (2010): 1161-169. Print.
Posted on Sun, 4 Dec 2011 11:54 PM MST by Michael A.

December 2, 2011

One gene to ruin them all: schizophrenia, bipolar, and DISC1

Discovered over a decade ago by scientists studying a Scottish family riddled with mental disorders, variations in the gene DISC1, or "discovered in schizophrenia-1", have been heavily linked to development of schizophrenia and, to a lesser extent, bipolar disorder. Only recently, however, have scientists begun unraveling the importance of the gene and its mechanistic functions. DISC1 encodes a scaffolding protein, a protein whose function is to help organize signaling pathways via formation of complexes with multiple other proteins in a way that allows them to interact. Experiments have shown the critical importance of DISC1 in a multitude of developmental functions, including neuronal migration, axonal and dendritic growth, and synaptogenesis, and neurogenesis, to name a few. Of the half-dozen or so DISC1-dependent signaling pathways discovered, a recent paper shows that disruptions in the Wnt pathway is implicated in a significant amount of the abnormal neurological features seen in persons with schizophrenia (and bipolar).

The Wnt pathway is critical for cell proliferation during development and plays key roles in embryogeneis, neuronal growth, and certain types of cancer. Activation of this pathway results in an increase of B-catenin, which associates with other proteins to upregulate transcription of certain genes necessary for proper neuronal development. Recent experiments have showed that schizophrenics and bipolar patients with genetic variations of the DISC1 gene show inhibited Wnt signaling and reduced neuroblastoma (N2a) cell proliferation. These studies also showed that the most common DISC1 variants had a decreased affinity for the protein GSK3-B, an intermediate in the Wnt pathway, to which it normally binds and inhibits. GSK3-B is responsible for the phosphorylation and subsequent degradation of B-catenin in the absence of Wnt signaling, and it is thought that in the absence of Wnt DISC1 is responsible for its inhibition. Since schizophrenic variations of DISC1 show a decreased affinity for GSK3-B, this may suggest a mechanism for the reduced signaling seen in many areas of the schizophrenic brain.

So why does any of this matter? Drug treatments. Lithium, the classic mood-stabilizing drug used to treat mania, was shown to inhibit GSK3-B just a little over a decade ago, and its mechanism of action is only now coming to light. Some antipsychotics have also been shown to indirectly stimulate the Wnt pathway, which might be a significant aspect of their pharmacological actions. With this knowledge in hand, selective inhibitors of GSK3-B (mimicking the actions of DISC1) or agonists for Frizzled, the Wnt receptor, could effectively attenuate many of the symptoms associated with schizophrenia and bipolar disorder. Along with brain imaging and genetic testing, disruptions in this pathway could also serve as an early marker for children predisposed for these mental disorders. Drugs such as those mentioned above could also prove useful in children with a high risk for developing schizophrenia or bipolar, in which an early drug regiment could blunt the onset of the disease and possibly prevent a lifelong struggle with a mental disorder. Although there are many other genes and pathways implicated in these cognitive disorders, the massive developmental impact of DISC1 variants and their effects on the Wnt pathway opens up promising new therapeutic opportunities for the treatment of schizophrenia and bipolar disorder.

Paper: "Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development", Singh et. al
Posted by      Kevin K. at 4:43 PM MST
  aidan mary  says:
feel regret I did not know this before I read your article, thank for sharing with us!
the impossible quiz
Posted on Tue, 27 Aug 2019 9:47 PM MDT by aidan m.

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