Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors.

Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinforcing reward pathways and modulating neuronal plasticity. Teneurin-4 (TENM4), a type II transmembrane protein, is essential for neural development and for establishing precise synaptic connectivity. However, the specific role of TENM4 in the nucleus accumbens (NAc) during METH-induced reward remains unclear. Here, we found that repeated METH exposure selectively increased TENM4 protein expression in the nucleus accumbens (NAc), prompting us to investigate its function using an AAV-CRISPR-mediated knockdown (TENM4KD) targeted to the NAc in mice. TENM4KD significantly attenuated the development of METH-induced conditioned place preference, without altering METH-induced hyperlocomotion. This behavioral deficit was paralleled by blunted dopamine dynamics; fiber photometry revealed impaired predictive DA signals during conditioning, and microdialysis confirmed a reduction in both basal and METH-evoked DA levels. Mechanistically, this impairment was not due to damage to dopaminergic neurons themselves but was linked to a loss of local GABAergic neurons within the medial NAc and a compensatory upregulation of the dopamine transporter (DAT). These findings uncover a critical role for TENM4 in maintaining the integrity of local NAc circuits that govern reward learning. Thus, TENM4 emerges as a potential molecular target for therapeutic intervention, as manipulating its expression in the NAc disrupts local inhibitory signaling and reduces METH-induced addictive behaviors.