O-GlcNAc transferase couples nutrient availability to synaptic plasticity in paraventricular neurons to regulate satiety.

Satiation is essential for energy homeostasis and is dysregulated in metabolic disorders like obesity and eating disorders such as anorexia nervosa. While satiation engages a large neural network across brain regions, how the communication within this network depends on metabolic fluctuations is unclear. This study shows that nutrient access can affect neuron-to-neuron communication in this network by regulating excitatory synaptic plasticity through O-GlcNAc transferase (OGT) in αCaMKII satiation neurons in the paraventricular nucleus (PVN). Using cell-specific knockout mice and electrophysiological recordings, we demonstrate that OGT deletion in PVNαCaMKII neurons increases input resistance and neuronal excitability while preserving basic membrane electrical properties. Strikingly, feeding triggered a robust 3.8-fold increase in excitatory synaptic input in wild-type neurons, whereas OGT-knockout neurons failed to exhibit this feeding-induced synaptic activation and instead displayed a paradoxical trend towards decreased synaptic activity upon food intake. Furthermore, OGT deletion destabilized glucose-dependent synaptic responses, with knockout neurons displaying maladaptive depression of excitatory transmission in conditions where stability is normally preserved. These findings establish OGT as a nutrient-sensitive modulator of synaptic plasticity that ensures appropriate satiation signaling by coupling metabolic state to synaptic plasticity.