Functional study of the role of SAPAP3 postsynaptic density protein on dorsolateral striatal cholinergic interneurons

PROJECT SUMMARY/ABSTRACT
Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disease listed in top 10 and top 15 most disabling
illnesses in women and men, respectively, according to the Lancet in 2017 and has a predicted prevalence of
2.3% in the United States. OCD is characterized symptomatically in humans by obsessive thought patterns
and compulsive motor behaviors. Synaptic deficits have been linked to psychiatric and neurodevelopmental
diseases, including OCD, but the influence of disease-linked synaptic proteins on cellular, circuit, and
behavioral outputs are incompletely understood. SAPAP3 is a synaptic protein, whose mutation is correlated
with OCD diagnosis in humans. Constitutive SAPAP3 deletion in mice produces compulsive motor grooming
behaviors, which are rescued by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and
striatum-localized SAPAP3 re-expression. The SAPAP3-deletion model of OCD, therefore, has symptomatic
as well as treatment validity and can be used to investigate cellular- and circuit-level striatal dysfunctions
underlying this compulsive motor phenotype. Preliminary evidence highlights striatal cholinergic interneurons
(ChIs) as a likely contributor of widespread striatal dysregulation in this model. These cells display increased
evoked release of Acetylcholine (ACh) in the SAPAP3-lacking striatum, which can modulate striatal circuits
through myriad subtypes of widely expressed ACh receptors. This proposal combines electrophysiology,
optogenetics, and 2-photon scanning laser microscopy (2PLSM) to test the overarching hypothesis, that
functional dysregulation of ChIs is tied to maladaptive striatal ACh release and compulsive motor behavior in
the SAPAP3-lacking model.
In (Aim 1), patch-clamp electrophysiology in ex vivo brain slices will be used to compare intrinsic ChI function,
and brain slice immunohistochemistry will be used to probe synaptic ACh release machinery. This will uncover
SAPAP3 deletion’s impacts on intrinsic functional properties related to ACh release by ChIs. (Aim 2) will
leverage viral optogenetic and ACh sensor constructs, electrophysiology, and 2PLSM to test for input-specific
changes to synaptically evoked striatal ACh release. Finally, (Aim 3) will selectively rescue SAPAP3
expression in ChIs to test if this model’s disrupted striatal ACh release and OCD-like phenotype are intrinsically
driven by SAPAP3-deletion in these cells. This will inform whether ChI-targeted therapies may be sufficient to
modify this OCD-like circuit and behavioral phenotype.

Grant Number: 5F30MH130078-04
NIH Institute/Center: NIH
Principal Investigator: Alexander Baez