12:00 AM
Aug 29, 2013
 |  BC Innovations  |  Tools & Techniques

DISCerning schizophrenia in mice

Despite genetic advances in schizophrenia research, a lack of predictive preclinical models has hampered the development of new therapeutics. Now, a team at The Johns Hopkins University has created a transgenic mouse model of prefrontal dysfunction involving disrupted networks of neurons that cause behavioral changes similar to those seen in patients with schizophrenia or mood disorders.1

The model may represent a useful tool for preclinical characterization of candidate compounds. It centers on the schizophrenia risk marker disrupted in schizophrenia 1 (DISC1) and represents a departure from traditional models that approach the disease as one rooted in an imbalance of neurotransmitters and receptors. Instead, it puts disrupted connectivity in the brain as the cause of schizophrenia.

An inherent problem in employing animal behavioral models in CNS drug development is the difficulty of recapitulating human higher functions such as decision making, emotion and adaptability. Indeed, the vast majority of compounds are evaluated in behavioral assays on normal rats, whose brains do not display the structural and biochemical changes that underlie the different psychoses in humans.

Creating representative models of diseases such as schizophrenia is particularly difficult because of the involvement of multiple genetic factors and environmental triggers. Even when genetic breakthroughs are made, reproducing genetic changes in rats remains technically challenging because of the difficulties of making rat-derived embryonic stem cells despite recent progress in the field.2

Michela Gallagher, professor of psychology and neuroscience at Johns Hopkins, and her group at the university have taken a different approach with a model that involves overexpression of an inactive, mutant form of Disc1.1

The gene has been strongly linked to schizophrenia predisposition following its identification in a Scottish family that suffered mental illnesses in several generations.3 The inactive mutant, a dominant negative form known as DN-DISC1, overrides the action of the regular DISC1 protein, which normally plays a role in the development and maintenance of synapses. Previous studies from other groups have suggested DISC1 is involved in synaptic regulation and the creation of networks that are disrupted in...

Read the full 1665 word article

User Sign in

Trial Subscription

Get a 4-week free trial subscription to BioCentury Innovations

Article Purchase

$100 USD
More Info >