The Molecular Role of C1QL3 and its Binding Partners in Synaptic Regulation

PROJECT SUMMARY
Neuropsychiatric disorders often cause lifelong disruptions of patients’ lives and lack satisfactory
pharmacological interventions. Symptoms in these disorders are likely associated with disruption in synapses
resulting from dysfunctional synaptic adhesion molecules (SAM), but the mechanisms by which SAMs may
contribute to synaptic dysfunction have not been fully elucidated. Complement C1q like 3 (C1QL3), is a promising
SAM for potential therapeutics for neuropsychiatric disorders because it selectively regulates excitatory
synapses and may therefore constitute a target for correction of the excitatory/inhibitory synaptic imbalances
associated with several neuropsychiatric disorders. To contribute to the future development of novel
therapeutics, I will elucidate the molecular mechanisms contributing to C1QL3’s roles in regulating excitatory
synapses. My preliminary data suggest that C1QL3 associates with the adhesion G protein-coupled receptor B3
and neuronal pentraxin 1 at synapses in mouse primary neuron cultures, consistent with our previous data
suggesting that these proteins promote cell-cell adhesion in heterologous cells in a C1QL3-dependent manner.
In Aim 1, I will test whether this hypothesized trans-synaptic adhesion complex truly forms at synapses in neuron
cultures, using super resolution microscopy. I will characterize the synaptic nano-architecture of this complex,
then determine the extent to which it is dependent on C1QL3 by knocking out C1QL3. I will further elucidate the
molecular interactions contributing to trans-synaptic adhesion through structure-function analysis using C1QL3
mutants that are not conducive to complex formation. This will elucidate the specific binding interactions that
contribute to C1QL3’s role in promoting synapse architecture and maintenance. In Aim 2, I will study how a novel
C1QL3 binding protein contributes to synaptic maintenance, potentially through its interactions with C1QL3. My
preliminary data suggest this novel protein increases excitatory synapse density in a C1QL3-dependent manner.
I will therefore determine this novel protein’s mechanism of synaptic regulation and the extent to which it
modulates the hypothesized C1QL3-mediated trans-synaptic adhesion complex. This study will provide insight
into the components of the molecular web of SAMs that regulate synapses and may highlight novel targets for
repairing synaptic dysfunction. Through this project I will develop and hone many skills that are essential for my
goal of becoming an independent physician-scientist at an academic institution. I am well supported in the
M.D./Ph.D. program at UConn Health by my sponsors and clinical mentors that will facilitate the successful
completion of this project and development into a promising physician-scientist.

Grant Number: 5F30MH135628-02
NIH Institute/Center: NIH
Principal Investigator: KEAVEN CARO