Developmental control of noradrenergic system by SLITRK1 and its implications in the pathophysiology of neuropsychiatric disorders

Abstract

SLITRK1 is a neuronal transmembrane protein with neurite development-and synaptic formation-controlling abilities. Several rare variants of SLITRK1 have been identified and implicated in the pathogenesis of Tourette’s syndrome, trichotillomania, and obsessive–compulsive disorder, which can be collectively referred to as obsessive–compulsive-spectrum disorders. Recent studies have reported a possible association between bipolar disorder and schizophrenia, including a revertant of modern human-specific amino acid residues. Although the mechanisms underlying SLITRK1-associated neuropsychiatric disorders are yet to be fully clarified, rodent studies may provide some noteworthy clues. Slitrk1-deficient mice show neonatal dysregulation of the noradrenergic system, and later, anxiety-like behaviors that can be attenuated by an alpha 2 noradrenergic receptor agonist. The noradrenergic abnormality is characterized by the excessive growth of noradrenergic fibers and increased noradrenaline content in the medial prefrontal cortex, concomitant with enlarged serotonergic varicosities. Slitrk1 has both cell-autonomous and cell-non-autonomous functions in controlling noradrenergic fiber development, and partly alters Sema3a-mediated neurite control. These findings suggest that transiently enhanced noradrenergic signaling during the neonatal stage could cause neuroplasticity associated with neuropsychiatric disorders. Studies adopting noradrenergic signal perturbation via pharmacological or genetic means support this hypothesis. Thus, Slitrk1 is a potential candidate genetic linkage between the neonatal noradrenergic signaling and the pathophysiology of neuropsychiatric disorders involving anxiety-like or depression-like behaviors.

Defects in early synaptic formation and neuronal function in Prader-Willi syndrome

“…The overexpression of SLITRK1 in hippocampal neurons promotes the formation of excitatory and inhibitory synapses 34 . SLITRK1 is associated with Tourette’s syndrome, which displays obsessive–compulsive disorder 36 , and SlITRK1 KO mice show behavioral abnormalities 37 . Our data on the downregulated expression of SLITRK1 in NDN KO and MAGEL2 KO neurons suggested that SLITRK1 could be a key regulator of synapse formation related to the ASD phenotype in PWS (Fig.…”

Large nesting expression in deer mice remains stable under conditions of visual deprivation despite heightened limbic involvement: Perspectives on compulsive‐like behavior

“…Given the impact of anxiety on clinical OCD symptomology, interest into the potential contributions of the noradrenergic system also increased in recent years (Hatayama & Aruga, 2023). However, since antidepressants with a noradrenergic mechanism of action are mostly ineffective in the treatment of OCD (Kellner, 2022), some background is needed.…”