The Aoto Lab is interested in investigating how differentially expressed and disease-relevant trans-synaptic cell-adhesion molecules (tsCAMs) are uniquely utilized in neural circuits implicated in neuropsychiatric disorders and drug addiction. To interrogate the function of tsCAMs with cell-type- and synapse-specific resolution, we employ multi-disciplinary approaches that include mouse genetics, in vivo stereotaxic injections of viruses to functionally trace circuits or manipulate gene expression, ex vivo slice electrophysiology, optogenetics, single-cell RNA-sequencing and super-resolution microscopy. We believe that by understanding cell-type- and synapse-specific tsCAM usage, we will provide critical mechanistic and synaptic insight into how genetic abnormalities in genes that encode for these molecules can result in synapse and circuit dysfunction that contribute to the etiologies that underlie mental health disorders and addiction.
Specifically, we will initially focus our attention on understanding how neurexin-3, a presynaptic tsCAM, functions in the context of poorly understood neural circuits relevant to schizophrenia and drug addiction. Neurexin-3 is encoded by the Nrxn3 gene, which is one of three evolutionarily conserved neurexin genes (Nrxn1-3). Neurexins share high sequence and structural homology and were thought to be redundantly utilized by all synapses in the CNS. However, we have recently demonstrated that neurexin-3 is strongly differentially expressed in distinct brain regions - even in different classes of neurons within the same brain region - and found that differential expression can confer Nrxn3 with the ability to govern key synaptic features. While mutations in individual Nrxn genes have been frequently associated with autism spectrum disorders and schizophrenia, Nrxn3 is the only neurexin gene to be repeatedly linked to BOTH schizophrenia and various forms of addiction (cocaine, opioid, nicotine and alcohol). The genetic linkage of Nrxn3 to schizophrenia and drug addiction suggests that presynaptic neurexin-3 plays an essential role in regulating synaptic transmission in circuits relevant to both disorders.
Interestingly, schizophrenia and drug addiction share a common pathophysiological basis - the dysregulation of the dopamine system. Pre-clinical and clinical evidence suggests that dysregulation of dopamine in patients afflicted by schizophrenia and/or drug addiction stems from hyperactivity of the ventral subiculum - a poorly understood structure that serves as the major output of the hippocampus. In the context of dopamine regulation, the ventral subiculum sends axons to and makes relatively uncharacterized synapses in the nucleus accumbens, located in the ventral striatum. Two on-going projects will test the hypothesis that Nrxn3 plays a dominant, non-redundant synaptic function in subicular circuits by probing the cell-type- and synapse-specific role of Nrxn3 in the subiculum-nucleus accumbens projection circuit and the subiculum local microcircuit. In addition, a third project focuses on performing an unbiased molecular characterization of distinct cell-types within the subicular circuitry to identify differentially expressed tsCAMs for future studies. We are also using super-resolution microscopy to understand how tsCAMs function to govern nanodomain architecture in the synaptic cleft. This project is in collaboration with the Double Helix Optics and the Advanced Light Microscopy Core in Boulder.
In Vivo Stereotaxic Injections and Imaging
Ex Vivo Acute Slice Electrophysiology