Abstract

The role of obsessive compulsive disorder-gene SLITRK5 in BDNF-dependent synaptic plasticity

Martinelli S, Lee FS
53rd Annual Meeting of the Society for Neuroscience. 2024.

Abstract

Background: Obsessive-compulsive disorder (OCD) is a psychiatric disorder marked by obsessive thoughts and repetitive actions, driven by genetic and environmental factors. Altered brain circuits, notably hyperactivity in the orbitofrontal cortex and striatum, are implicated. The underlying molecular mechanisms that produce these alterations are, however, not well understood. Genetic studies have begun to identify major risk genes related to OCD, with a significant focus on Slitrk5, a TrkB co-receptor, involved in synapse formation and neurotrophic signaling as well as glutamate transmission and neuronal excitability. Recent findings also indicate a complex interaction between TrkB and mGluR5 receptors, suggesting a novel mechanism by which neurotrophic signaling can affect glutamate transmission and neuronal excitability. These findings highlight the critical role of glutamate signaling and neuronal plasticity in understanding the molecular mechanisms underlying OCD symptoms and the potential bridging role of Slitrk5.

Aim: We aim to elucidate Slitrk5's role in synaptic transmission, impacting neurotrophic and glutamatergic signaling, potentially underlying cortical hyperactivity in OCD.

Methods: Using both human cell lines and cultured primary mouse neurons, we use a combination of targeted and unbiased approaches. We adopt functional and biochemical assays in association with genetic and pharmacological perturbations to determine the molecular action mechanism of Slitrk5 in response to brain-derived neurotrophic factor (BDNF). In parallel, we carry out a Slitrk5 interactome analysis through which we identify key players involved in the BDNF-TrkB-Slitrk5 signaling pathways as well as expand the repertoire of potential treatment targets for next generation OCD treatments.

Results: We generated a stable Slitrk5 expressing 293HEK line to have a suitable model to investigate the function and trafficking of this TrkB co-receptor at baseline and in response to BDNF. In line with previous literature, we found that Slitrk5 perturbs the BDNF-induced TrkB pathway via calcium imaging. Ongoing interactome analyses will further elucidate the kinetic and signaling dynamic.

Conclusions: This study will help elucidate how the OCD-related gene Slitrk5 influences neurotrophic signaling pathways and glutamatergic transmission, potentially explaining cortical hyperactivity in OCD. Additionally, identified interactors from proteomics may uncover new key players underlying OCD mechanisms and new potential treatment targets for OCD-symptom-specific treatments.