INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are widely used in the treatment of type 2 diabetes and obesity, with an increasing prevalence of off-label use. In addition to their metabolic effects, GLP-1RAs affect the function of the central nervous system. Emotional regulation, cognitive processes and reward-related behaviour are all significant functions of the medial prefrontal cortex (mPFC). However, semaglutide’s impact on synaptic plasticity in this region of the brain remains uncertain.

AIM(S): To evaluate the effects of semaglutide on synaptic transmission and plasticity in the medial prefrontal cortex in mice.

METHOD(S): Semaglutide (3 nmol/kg) or physiological saline was administered to C57BL/6 mice on a daily basis for a period of 10 days. Electrophysiological recordings were conducted in acute mPFC slices subsequent to treatment. Paired-pulse facilitation (PPF), long-term potentiation (LTP) and basal synaptic transmission were evaluated. The experiment included the monitoring of body weight.

RESULTS: No significant changes were observed in baseline synaptic transmission or PPF between groups. However, the mPFC of semaglutide-treated mice exhibited a substantial decrease in LTP induction compared to controls, suggesting that synaptic plasticity was compromised. Additionally, semaglutide administration led to reduced body weight gain.

CONCLUSIONS: Semaglutide disrupts LTP induction in the medial prefrontal cortex, which implies that it may have an impact on reward-related circuitry and synaptic adaptability. These findings highlight the need for further research into the long-term neurophysiological effects and safety profile of GLP-1RAs within the central nervous system, particularly given their expanding clinical and off-label use.