Novel modulators of Arc function for the development of pro-cognitive therapeutics in neuropsychiatric disorders

Stephanie Santarriaga, PhD

Massachusetts General Hospital
Novel modulators of Arc function for the development of pro-cognitive therapeutics in neuropsychiatric disorders

Scientific Abstract

 

Background: There is convergent genetic evidence for the involvement of multiple components of the Arc (Activity-regulated cytoskeleton-associated protein; Arg3.1) protein complex in glutamatergic dysregulation in neuropsychiatric disorders. Functional studies of the consequence of loss of Arc on synaptic plasticity and memory consolidation in rodent systems further suggest that deficits in Arc may contribute to the pathophysiology of cognitive impairments in neuropsychiatric disorders. Conversely, overexpression of Arc has been shown to increase dendritic spine density and to restore plasticity in the adult cortex in animal studies. However, much of our understanding of Arc and synaptic plasticity stems from rodent models. Here, we utilize chemical biology approaches to identify Arc potentiators that be used to delineate Arc function and modulate synaptic plasticity in human neurons.

Methods: To begin, we conducted a high-content, image-based screen of a library of approved drugs and known bioactive small molecules in mouse cortical neurons to identify potentiators of neuronal activity-dependent induction of Arc protein. To determine if these results would translate to human cells, we analyzed Arc in human cortical neurons differentiated from induced pluripotent stem cells (iPSCs) of schizophrenia subjects and healthy subjects. We then performed a preliminary structure-activity relationship assay to identify small molecules that modulate Arc levels and increase synaptic plasticity.

Results: We identified lurasidone as the greatest potentiator of Arc levels in mouse cortical neurons. In human cortical neurons, lurasidone increased Arc protein levels and dendritic spine number. Interestingly, Arc localization in the human cortical neurons differed from the mouse cortical neurons suggesting potential differences in Arc function.

Conclusions: Our studies identified potentiators of Arc that will enable dissection of Arc biology in synaptic function in human neurons. These small molecules will also assist in our studies investigating how Arc modulation may ameliorate cognitive deficits in neuropsychiatric disorders.

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research Areas

Authors

Stephanie Santarriaga, PhD, Kaia Gerlovin, BS, Surya Reis, PhD, Jasmin Lalonde, PhD, Stephen J. Haggarty, PhD, Rakesh Karmacharya, MD, PhD