Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities

Abstract

Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an a2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plusmaze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…Studies with knockout mice have revealed probable associations of Slitrks with neuropsychiatric disorders. Slitrk1-null mice display increase anxiety-like behavior (quantified by the elevated plus-maze test) as well as depressive-like behaviors (assessed in a forced-swim task) (Katayama et al, 2010). Neurochemical analysis revealed that Slitrk1-deficient mice have increased levels of norepinephrine in the prefrontal cortex, striatum, and nucleus accumbens, a finding that is consistent with the pathophysiology of GTS.…”

“…Slitrks have been implicated in the modulation of neurite outgrowth Katayama et al, 2010;Martyen et al, 2011), the promotion of neuron survival (Katayama et al, 2009), and synapse formation (Proenca et al, 2011). Overexpression of each Slitrk member, except Slitrk1 or -4, was shown to decrease the number of neurites in PC12 cells upon nerve growth factor (NGF) treatment .…”

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

“…[47][48][49][50] Among LRR proteins, LRFNs form a family of transmembrane cell adhesion molecules that promote changes in neuronal morphology, dendritic outgrowth and synapse formation. [51][52][53] It was further demonstrated that LRFNs form complexes with NMDARs, and promote the specialization of excitatory synapses.…”

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

“…For example, Slitrk1 variants are linked to the spectrum of obsessive-compulsive disorders (OCDs), Tourette syndrome, and trichotillomania (7,8), and Slitrk2 is associated with schizophrenia and bipolar disorder (9,10). Moreover, Slitrk1 mutant mice show anxiety-like behaviors and Slitrk5-deficient mice display OCD-like behaviors (11,12). Recently, Slitrk3 was shown to control inhibitory synapse development selectively (13).…”