Deficiency of the Synaptic Adhesion Protein Leucine-Rich Repeat Transmembrane Protein 4 Like 1 Affects Anxiety and...

Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic adhesion proteins that regulate synapse development and function. They interact transsynaptically with presynaptic binding partners to promote presynaptic differentiation. Polymorphisms of LRRTM4, one of the four members of this protein family, have been linked to multiple neuropsychiatric disorders and childhood aggression, but the underlying mechanisms and physiological function of LRRTM4 during behavior are currently unclear.

To characterize the role of this gene for brain function, we combined a battery of behavioral assays with transcriptomic and metabolomic analyses, using zebrafish as a model system.

Our findings revealed that lrrtm4l1, a brain-specific zebrafish orthologue of human LRRTM4, exhibits a brain region-specific expression pattern similar to humans, with strong expression in the dorsal telencephalon, a brain area critical for regulating emotional-affective and social behavior. lrrtm4l1^-/- zebrafish displayed heightened anxiety and reduced aggression, while locomotion and social behavior remained unaffected by the gene knockout. Transcriptomic analysis of the telencephalon identified over 100 differentially expressed genes between wild-type and mutant zebrafish and an enrichment of pathways related to synaptic plasticity and neuronal signaling. The brain metabolome of lrrtm4l1^-/- zebrafish showed multiple alterations, particularly in the dopaminergic and adenosinergic neurotransmitter systems.

These findings suggest that LRRTMs may have functions beyond their established role in excitatory synapse development, such as the regulation of neurotransmission and behavior. Targeting LRRTM4 therapeutically may thus be an interesting novel approach to alleviate excessive aggression or anxiety associated with a number of neuropsychiatric conditions.