Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome

Abstract

Tourette syndrome (TS) is an inherited developmental neuropsychiatric disorder characterized by vocal and motor tics. Multiple lines of neurophysiological evidence implicate dysfunction in the corticostriatal-thalamocortical circuits in the etiology of TS. We recently identified rare sequence variants in the Slit and Trk-like family member 1 (SLITRK1) gene associated with TS. SLITRK1, a single-pass transmembrane protein, displays similarities to the SLIT family of secreted ligands, which have roles in axonal repulsion and dendritic patterning, but its function and developmental expression remain largely unknown. Here we provide evidence that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal-thalamocortical circuits. SLITRK1 is further enriched in the somatodendritic compartment and cytoplasmic vesicles of cortical pyramidal neurons in mouse, monkey, and human brain, observations suggestive of an evolutionarily conserved function in mammals. SLITRK1 is transiently expressed in the striosomal/patch compartment of the mammalian striatum and moreover is associated with the direct output pathway; adult striatal expression is confined to cholinergic interneurons. These analyses demonstrate that the expression of SLITRK1 is dynamic and specifically associated with the circuits most commonly implicated in TS and related disorders, suggesting that SLITRK1 contributes to the development of corticostriatal-thalamocortical circuits.

Neurocognitive Aspects of Tourette Syndrome and Related Disorders

“…SLITRK1 expression was confirmed in cortical striatal circuits, which is consistent with regions implicated in GTS pathology (Stillman et al, 2009). An animal model of SLITRK1 deficiency shows altered noradrenergic function phenotype related to alpha-agonists, which are used in the treatment of Tourette syndrome (Katayama et al, 2010).…”

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

“…Indeed, genetic mutations of a subset of Slitrks have been associated with multiple neuropsychiatric diseases (7,9,10). In support of this idea, Slitrk1 is expressed in neural circuits of basal ganglia implicated in Tourette syndrome (35). Although many neuropsychiatric disorders, particularly autism spectrum disorders, are thought to occur as a result of an imbalance between excitatory and inhibitory synapses, whether the spectrum of OCDs reflects a similar excitatory-inhibitory imbalance has not yet been established (36).…”

Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families

“…3 It has been shown to control neurite outgrowth and it is expressed in the embryonic and postnatal brain, including the cortex, thalamus and the basal ganglia, reflecting the neuroanatomical regions most commonly implicated in TS. 4 By studying mouse, monkey and human brains, Stillman et al 5 recently showed that SLITRK1 expression in the striatum is high during early brain development but significantly diminished later. This suggests a possible role of SLITRK1 in establishing the corticostriatal circuitry, in concordance with the neurodevelopmental hypothesis for TS etiology.…”