Biology subjects

Lagerlof, O.

Publications and source records attributed to Lagerlof, O..

3 recordsLinked to original sources

bioRxiv2025

O-GlcNAc Transferase Regulates GABAergic Synapse Organization and Receptor Composition.

Neural circuits must integrate metabolic information to maintain stable activity and appropriate behavioral responses. While metabolic regulation of excitatory synapses has been well studied, far less is known about how inhibitory synapses respond to changes in energy state. In this study, we show that O-GlcNAc transferase (OGT), a dynamic sensor of cellular nutrient flux, localizes to postsynaptic sites of the inhibitory synapses where it modulates synapse morphology and receptor composition. OGT over-expression reduced the size and intensity of vGAT and gephyrin puncta, whereas conditional OGT deletion produced a converse enlargement and redistribution of inhibitory scaffolds and vesicular proteins. Furthermore, OGT deletion accelerated inhibitory postsynaptic current decay kinetics and induced subunit-specific shifts in GABAA receptor surface expression: {beta}3 subunits decreased, whereas {gamma}2 subunit total and surface levels increased. Together, these findings identify OGT as a metabolic regulator that modulates inhibitory synapse structure and signaling, providing a mechanistic link between energy state and GABAergic circuit function in health and disease.

neuroscience↗

bioRxiv2025

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.

neuroscience↗

bioRxiv2025

Somatostatine interneurons mediate dopamine-dependent sensory gating in the orbitofrontal cortex

The prefrontal cortex continuously filters irrelevant stimuli, and deficits in this sensory gating predispose to psychotic disorders. In schizophrenia, the normally observed suppression of second response to two paired sounds is drastically reduced. Apart from sensitivity to critical schizophrenia players as NMDA and dopamine, the microcircuitry behind gating remains unknown. We found that the first sound excitatory response recruits, via NMDA receptors, local inhibition to gate the second response via GABAB receptors. Optogenetic inhibition of somatostatine-interneurons counteracted gating more effectively compared to parvalbumine-positive interneurons. Dopamine local blockade also counteracted gating, and dopamine effect was prevented by somatostatine-, but not parvalbumine-, optoactivation. Thus, prefrontal gating is mediated by NMDA-dependent recruitment of dendrite-targeting, somatostatine-interneurons, facilitated by dopamine. The results identify a critical synapse to better target psychose-prone disorders.

neuroscience↗