Neuropsychiatric disorders are the leading cause of disease burden in the United States and Canada, far outpacing other maladies such as cardiovascular disease and cancer (WHO statistics). Progress in treating neuropsychiatric disorders is severely hampered by our lack of basic knowledge related to their underlying causes. Defects in dendritic spine morphogenesis, a process regulated by dynamic actin remodeling, is a common feature of these disorders and is also associated with stress, which may precipitate disorders such as schizophrenia. Moreover, it is increasingly clear that disruptions in genes that regulate signaling to excitatory synaptic actin are risk factors for schizophrenia, autism, and intellectual disability. Arp2/3 complex is enriched in dendritic spines and stimulates the formation of branched actin downstream of many genes implicated neuropsychiatric disorders. Recently we published that the conditional loss of Arp2/3 in mice leads to the progressive development of multiple synaptic and behavioral phenotypes relevant to models of schizophrenia. Many of the schizophrenia-related behaviors are normalized by the antipsychotics clozapine and haloperidol.
The specific aims of this grant build on these exciting findings to address fundamental questions of how SZ-related phenotypes evolve at the synaptic and circuit level and how this is influenced by chronic stress. We anticipate the results of these aims will bridge our knowledge gap regarding how SZ-like phenotypes emerge in vivo, leading to new future directions for the prevention and possible treatments of the disorder.
Genetic evidence suggests that an accumulation of genetic interactions between multiple allelic variants can predispose individuals to schizophrenia (SZ), implying that SZ is a signaling network or pathway disorder. The realization that disorders such as SZ are genetically heterogeneous presents a formidable problem. However, there is hope that identifying mutations associated with SZ may lead to the identification of pathways that are commonly disrupted in the illness. Unfortunately, pathway disorders are difficult to model by mutation of single regulatory nodes due to the highly connected and compensatory nature of most biological networks. Thus an innovative and informative approach is to conditionally target the final downstream output of multiple pathways implicated in SZ. This approach can clarify which pathways are likely to contribute to individual features of the disorder. Recently we demonstrated that abnormal signaling to Arp2/3 is one such pathway, and that the disruption of Arp2/3 can recapitulate the functional manifestations of many upstream candidate genes previously associated with SZ. We are now in a position to answer fundamental questions of how dysregulated Arp2/3 activity leads to synaptic and behavioral SZ-like phenotypes. Understanding of the neurobiology underlying the onset and progression of SZ is highly relevant to the mission of NIH.
|Spence, Erin F; Kanak, Daniel J; Carlson, Benjamin R et al. (2016) The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing. J Neurosci 36:9696-709|
|Yan, Zhen; Kim, Eunjoon; Datta, Dibyadeep et al. (2016) Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders? J Neurosci 36:11411-11417|
|Rossi, Mark A; Li, Haofang E; Lu, Dongye et al. (2016) A GABAergic nigrotectal pathway for coordination of drinking behavior. Nat Neurosci 19:742-748|
|Singh, Sandeep K; Stogsdill, Jeff A; Pulimood, Nisha S et al. (2016) Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1? and NL1 via Hevin. Cell 164:183-196|
|Kim, Il Hwan; Rossi, Mark A; Aryal, Dipendra K et al. (2015) Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. Nat Neurosci 18:883-91|
|Spence, Erin F; Soderling, Scott H (2015) Actin Out: Regulation of the Synaptic Cytoskeleton. J Biol Chem 290:28613-22|
|Zuchero, J Bradley; Fu, Meng-Meng; Sloan, Steven A et al. (2015) CNS myelin wrapping is driven by actin disassembly. Dev Cell 34:152-67|
|Kim, Il Hwan; Wang, Hong; Soderling, Scott H et al. (2014) Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall. Elife 3:|
|Risher, W Christopher; Patel, Sagar; Kim, Il Hwan et al. (2014) Astrocytes refine cortical connectivity at dendritic spines. Elife 3:|