Jason Aoto, PhD

Assistant Professor


 
Jason Aoto

Contact Information:

University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-North
12800 East 19th Ave
Aurora CO 80045

Phone: (303) 724-9302
Fax: (303) 724-3663

Office: RC1-North, P18-6101

curriculum vitae​​

 
​​​A fundamental question in molecular neuroscience is: how are properties of synapses (basic units of information storage) defined, formed, stabilized, maintained and modulated? Synaptic cell-adhesion molecules likely play critical roles at the synapse because they: i.) transsynaptically interact, in a poorly understood combinatorial manner, to physically couple the presynaptic axon and postsynaptic dendrite; and ii.) recruit key synaptic molecules (e.g. ion channels, ligand-gated receptors, scaffolding proteins) and/or initiate intracellular signaling cascades (e.g. kinases and small GTPase) in their respective cell. Thus, it is not surprising that genomic abnormalities in genes that encode for these molecules are frequently associated with neuropsychiatric disorders (Autism spectrum disorders (ASDs), schizophrenia, attention deficit/hyperactivity disorder and intellectual disability) and addiction (cocaine, opioid, alcohol and nicotine). It is essential to understand how synaptic cell-adhesion molecules are utilized in disease-relevant circuitry and how their dysfunction can contribute to the synaptic etiologies that underlie mental health disorders. Recent technological advances now allow the study of molecule function in distinct neural circuits with cell-type- and synapse-specific resolution to ultimately gain greater insight into how synaptic cell-adhesion molecules function.

Our laboratory is interested in interrogating how synaptic cell-adhesion molecules function to shape cell-type- and synapse-specific synaptic transmission properties in the context of disease-relevant neural circuitry. Specifically, we are currently interested in dissecting the function of a family of essential presynaptic molecules called the neurexins. The mammalian genome houses three evolutionarily conserved, and structurally similar, neurexin genes (Nrxn1-3) that are frequently altered in human patients with mental health disorders. Interestingly, mutations unique to Nrxn3 are associated with both drug addiction and schizophrenia, which strongly suggests that neurexin-3 plays a dominant and non-redundant function to shape synapse functions in circuits implicated in both disorders. Schizophrenia and addiction are thought to share similar pathophysiological features - namely hyperactivity of the dopamine system. We will test the hypothesis that neurexin-3 (and other synaptic cell-adhesion molecules) plays a unique and dominant function at synapses in neural circuits that regulate dopamine levels in the brain.

We utilize cutting-edge multidisciplinary techniques that include: acute slice electrophysiology, animal behavior, stereotaxic injection of virus into targeted brain regions, functional circuit tracing viruses, optogenetics, molecular biology, mouse genetics and fixed and live cell imaging to dissect disease-relevant circuitry with unparalleled cell-type and synapse specific resolution. We are also keenly interested in applying single-cell next generation RNA sequencing (RNAseq) approaches to gain a molecular handle on poorly understood cells in the hippocampal formation and in the striatum. We hope that RNAseq will also identify candidate cell-adhesion molecules for future studies, where we will test function by applying CRISPR/cas9 technology to acutely alter candidate gene expression.​

Selected Peer-reviewed publications:

Pak CH*, Danko T*, Aoto J, Anderson GR, Maxeiner S, Wernig M, Südhof TC. Human Neuropsychiatric Disease Modeling using Conditonal Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1. (2015) Cell Stem Cell. 17(3):316-328. PMID: 26279266

* Co-first author

 

Anderson GR, Aoto J, Tabuchi K, Földy C, Covy J, Yee AX, Wu D, Chen L, Malenka RC, Südhof TC. (2015) Presynaptic b-Neurexins Control Excitatory Synaptic Strength and Regulate Synaptic Endocannabinoid Signaling. Cell. 162(3): 593-606. PMID: 26213384

 

Aoto J.#, Földy C, Ciurea-Ilcus SM, Tabuchi K, Südhof TC. (2015) Distinct Circuit-Dependent Essential Functions of Neurexin-3 in Regulating Presynaptic Release or Postsynaptic AMPA-Receptor Stability. Nature Neuroscience. 18(7): 997-1007. PMID: 26030848

            #Corresponding Author

 

Chanda S, Aoto J, Lee SJ, Wernig M, Südhof TC. Pathogenic Mechanism of an Autism-Associated Neuroligin Mutation Affects AMPA-Receptor Trafficking. Molecular Psychiatry. PMID: 25778475

 

Aoto J., Martinelli, DC, Tabuchi H, Malenka RC, Südhof TC. (2013) Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell, 154: 75-88. PMID: 23827676

 

Anderson GR, Galfin T, Xu W, Aoto J, Malenka RC, Südhof TC. (2012) Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. PNAS, 109: 18120-18125. PMID: 23074245

 

Sarti F, Schroeder J, Aoto J, Chen L. Conditional RARa knockout mice reveal acute requirement for retinoic acid and RARa in homeostatic plasticity. (2012) Front Mol Neurosci. PMID: 22419906

 

Aoto J*, Nam, CI*, Poon MM*, Ting P, and Chen L. (2008) Synaptic scaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron, 60: 308-220. PMID: 18957222

            *Equal Contribution

 

Maghsoodi B, Poon MM, Nam CI, Aoto J, Ting P, and Chen L. (2008) Retinoic acid regulates RARa-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity. Proc Natl Acad Sci U S A, 105: 16015-20. PMID: 18840692

 

Aoto J, Ting P, Maghsoodi B, Xu N, Henkemeyer M, and Chen L. (2007) Postsynaptic ephrinB3 promotes shaft glutamatergic synapse formation. J. Neurosci, 27: 7508-19. PMID: 17626212

 

 

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