Neuropsychiatric Disorders and Cell Signaling

By: Carolyn Crankshaw, Product Specialist, Sigma® Life Science, Biofiles, Vol. 8, No. 10

Schizophrenia, the most common psychotic disorder, affects ~ 25 million people worldwide and is one of the leading causes of years lived with disability.1 Historically, antipsychotic drug discovery has been serendipitous, resulting in treatment of a subset of symptoms while failing to address other dimensions of the disease such as cognitive deficits.2 Indeed, an understanding of the etiopathology of schizophrenia has proven elusive, despite the financial and societal impact of it and other neuropsychiatric disorders.

Fortunately, many recent advances in the ability to analyze the molecular basis of biological functions are opening the door to a new understanding of the molecular underpinnings of this intractable disease. Genetic analysis of a large Scottish family with a prevalence of psychiatric diseases revealed a balanced translocation in the disrupted in schizophrenia 1 (DISC1) gene that segregated with major mental disorders, including schizophrenia, bipolar disorder, and major depression.2,3 Subsequent studies of the biological function of DISC1 demonstrated multiple protein binding partners, characterization of which revealed DISC1 to have major regulatory roles in early brain development as well as in synapse formation and maintainance.2

An important advance in understanding the role DISC1 plays in neurodevelopment came with the discovery that DISC1 interacts with glycogen synthase kinase 3 (GSK3). GSK3 functions as a key regulator in several neurodevelopmental processes, and changes in activity have been associated with multiple psychiatric and neurodegenerative diseases, including schizophrenia.4 Knockdown of DISC1 in neural progenitor cells results in premature differentiation, an effect that can be prevented by administration of pharmacological inhibitors of GSK3. Co-expression of a degradation-resistant β-catenin abrogates the effects of DISC1 knockdown both in vitro and in vivo.5 DISC1 interaction with GSK3 therefore modulates Wnt-mediated proliferation, and these interactions as well as expression levels for both DISC1 and GSK3 have been shown to vary in a coordinated way during the course of embryonic development.2,4,5

DISC1 also plays a critical role in synaptic regulation. The post-synaptic compartment of excitatory synapses in the brain resides in dendritic spines, and deficits in dendritic spines as well as in glutamatergic neurotransmission occur in a number of mental illnesses with which DISC1 is genetically associated. DISC1 has been found localized to the synapse in post-mortem human cortex samples, and is enriched in the postsynaptic density fraction resulting from subcellular fractionation. Synaptic pathology is seen in many DISC1 mouse models that display behavioral deficits relevant to neuropsychiatric disorders. On the molecular level, several DISC1 interacting proteins function at the synapse. These include kalirin 7 (KAL7), which is reduced in autopsied brain of patients with schizophrenia, and TRAF-2- and NCK-interacting kinase (TNIK), linked to schizophrenia by genome-wide association studies and shown to function in conjunction with DISC1 to maintain synapse structure.2

Understanding the molecular mechanisms associated with neuropsychiatric disorders such as schizophrenia allows mapping of those pathways to effects on neuronal circuitry, and to behavioral and cognitive processes. Correlation of effects in all three domains sets the stage for a revitalized psychiatric drug discovery approach,6 and will be necessary to bring relief to the millions of people suffering from these debilitating diseases worldwide.

Materials

     

 References

  1. World Health Organization web site.
  2. Brandon, NJ and Sawa, A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nature Rev. Neurosci., 12, 707-722(2011).
  3. Soares, DC, et al. DISC1: Structure, function and therapeutic potential for major mental illness. ACS Chem. Neurosci., 2, 609-632 (2011).
  4. Hur, EM and Zhou, FQ. GSK3 signalling in neural development. Nature Rev. Neurosci., 11, 539-551 (2010).
  5. Mao, Y, et al. Disrupted in Schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136, 1017-1031 (2009).
  6. Sarter, M and Tricklebank, M. Revitalizing psychiatric drug discovery. Nature Rev. Drug Discovery 11, 423-424 (2012).

 

Related Links