Satiation is associated with OGT-dependent regulation of excitatory synapses.
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 CaMKII satiation neurons in the paraventricular nucleus (PVN). Using cell-specific knockout mice and electrophysiological recordings, we demonstrate that OGT deletion in PVNCaMKII neurons increases input resistance and neuronal excitability while preserving basic membrane electrical properties. Strikingly, feeding triggered a robust 3.8-fold increase in the excitatory synaptic input in wild-type neurons, whereas OGT-knockout neurons failed to exhibit this feeding-induced synaptic activation, instead displayed a paradoxical trend towards increases in synaptic activity during hungry conditions. 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 signalling by coupling metabolic state to synaptic plasticity.