Using CRISPR-Cas9 to correct mutations in hiPSC from patients with schizophrenia who have mutations in DLG2

Using CRISPR-Cas9 to correct mutations in hiPSC from patients with schizophrenia who have mutations in DLG2

By 01/10/2017 No Comments

Using CRISPR-Cas9 to correct mutations in hiPSC from patients with schizophrenia who have mutations in DLG2

Edward Nendick at the University of Edinburgh will be using one of the latest cutting edge, gene editing technologies, CRISPR-Cas9, in cell culture to further our understanding of schizophrenia without using mice.

SUPERVISOR: Dr Mandy Johnstone – University of Edinburgh

STUDENT: Mr Edward Nendick

Schizophrenia is a common devastating condition and whilst partially effective treatments are available, none are disease-modifying. There is a need for novel models of mental illness in human-derived cells to develop more effective therapies. Schizophrenia-derived human induced pluripotent stem cells (hiPS) models have demonstrated neuronal phenotypes representing powerful proof of concepts of in vitro disease modeling, even for diseases with complex causation such as schizophrenia. These techniques are being used by our lab to examine the behavior of neurons derived from fibroblasts from subjects carrying DLG2 copy number variations (CNVs) associated with increased risk of major mental illness. DLG2 is involved in the regulation of post-synaptic density proteins and glutamate receptor expression. DLG2 CNVs segregate with SCZ and cognitive deficits in families we are studying.

Using human induced pluripotent stem cells (hiPS) from individuals with and without disease-associated CNVs we are investigating how disease risk is conferred at a cellular level through detailed comparative studies of neuronal physiology and synaptic function and glutamate (NMDA) receptor expression. By correcting the disease-associated mutation our hypothesis is that we will be able to correct the electrophysiological deficits in the patient-derived neurons and thereby rescue the cellular phenotypes associated with disease.

Animal models of schizophrenia have reiterated some of the behavioural traits, neuronal phenotypes and molecular signatures associated with schizophrenia and have been used in the study of connectivity and function of specific neural networks in disease (Chen et al., 2006). As initial risks for schizophrenia occur during neurodevelopment, almost 20 years before full development of pathology occurs, it is difficult to study disease pathogenesis in human studies as brain biopsies from live patients face many clinical implications. However, findings from animal studies have limited potential. Communicating findings from animal models into effective therapeutics is often unsuccessful, mainly due to developmental, biochemical, metabolic and physiological differences in humans (Chen et al., 2006). A key weakness of animal studies is that some neocortical areas involved in psychiatric disorders are present only in humans (Nestler & Hyman, 2009). Moreover, rodents and human brains are distinctive in development and structure; mice are lissencephalic, whereas the human cortex has complicated sulci and gyri (Rakic, 2009). Rodents also have far less-developed prefrontal and temporal cortices. These regions are particularly important in the context of complex neuropsychiatric diseases (Rakic, 2009). Furthermore, it is difficult to evaluate classic symptoms such as delusions or hallucinations in mice (Clowry et al., 2010).

REFERENCES: Brennand K et al., Modeling Heterogeneous Patients With a Clinical Diagnosis of Schizophrenia With Induced Pluripotent Stem Cells. Biological Psychiatry. 2014 June;75(12): 936-944. Chen J et al., Genetic Mouse Models of Schizophrenia: From Hypothesis-Based To Susceptibility Gene-Based Models. Biological Psychiatry. 2006;59(12): 1180-1188. Nestler EJ et al., Animal models of neuropsychiatric disorders. Nature Neuroscience. 2010 Oct;13(10): 1161-1169. Rakic P. Evolution of the neocortex: a perspective from developmental biology. Nature Reviews Neuroscience. 2009;10(10): 724-735. Clowry G et al., Development of the human neocortex. Journal of Anatomy. 2010 Oct;217(4): 276-288.

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