Tacr3-KO Mouse

Tacr3 encodes tachykinin receptor 3 (NK3R), belonging to the tachykinin receptor family within the rhodopsin subfamily of G protein-coupled receptors. It functions by binding to its high-affinity ligand, neurokinin B (NKB), and is involved in the neuroendocrine control of GnRH release, playing a significant role in growth and reproduction. Also, it is widely expressed in the nervous system from the spinal cord to the brain, participating in numerous physiological and pathological nervous system processes [1].

In a mouse model of trigeminal neuralgia, Tacr3 in the lateral habenula was found to play a protective role. Down-regulation of Tacr3 was observed in the lateral habenula of mice with orofacial allodynia and anxiety-like behaviors induced by partial transection of the infraorbital nerve. Rescuing this down-regulation by overexpressing Tacr3 significantly reversed the anxiety-like behaviors but not allodynia. Bilateral Tacr3 overexpression or chemicogenetic inhibition of bilateral lateral habenula neurons alleviated both allodynia and anxiety-like behaviors, suggesting that Tacr3 suppresses the hyperexcitability of lateral habenula neurons [3]. In rats, severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus. TACR3 expression is sensitive to sex hormones, and its modulation significantly influences synaptic activity. Deficient TACR3 activity leads to lower serum testosterone levels, increased spine density, and impaired long-term potentiation in the dentate gyrus [2]. Mutations in TACR3 can disrupt NK3R function through distinct mechanisms. For example, certain mutations in the fifth and sixth transmembrane domains result in reduced whole-cell or plasma membrane levels of the receptor, nearly completely losing inositol phosphate signaling, while a mutation in the third intracellular loop impairs dissociation of Gq-protein subunits from the receptor [4]. Compound heterozygous mutations in TACR3 in siblings were associated with normosmic congenital hypogonadotropic hypogonadism [5].

In conclusion, Tacr3 plays crucial roles in both reproductive and nervous system-related biological processes. Research using mouse models has revealed its significance in conditions such as trigeminal neuralgia-associated mood disorders, anxiety-related synaptic plasticity, and reproductive disorders like hypogonadotropic hypogonadism. Understanding Tacr3 can provide insights into the underlying mechanisms of these diseases and potentially lead to new therapeutic strategies.