Presynaptic suppression of higher-order thalamocortical and corticocortical inputs to mouse somatosensory cortex

Long-range, higher-order communication within the neocortex is generally thought to provide necessary internal and contextual signals to influence local cortical dynamics during cognitive processes like attention, prediction, and awareness. How this long-range communication is influenced by arousal state, which entails a global modulation of brain activity during different behavioral contexts, is unclear. This may occur by recruiting layer 1 (L1), where long-range, higher-order pathways and neuromodulatory systems converge on GABAergic inhibitory circuits. L1 neuron-derived neurotrophic factor (NDNF)-expressing cells are particularly interesting given that they are engaged in high arousal states and their output is known to activate metabotropic gamma-aminobutyric acid (GABA) receptors, also known as GABAB receptors, which are often found on presynaptic terminals and influence release probability. Here, we used the mouse vibrissal primary somatosensory cortex (vS1) to understand the extent to which presynaptic inhibition occurs in long-range, higher-order pathways originating from the vibrissal primary motor (vM1) and secondary somatosensory cortex (vS2) as well as the posterior medial nucleus of the thalamus (POm) and the involvement of L1 GABAergic cells. Combining in vitro whole-cell electrophysiological recordings with optogenetic and pharmacological manipulation, we report that glutamate release from vM1 and vS2 axons targeting L2 pyramidal neurons in vS1 is robustly inhibited following activation of GABAB receptors (baclofen), whereas glutamate release from POm axons was not, suggesting pathway specificity. The GABAB-mediated suppression of glutamate release from long-range, higher-order corticocortical projections was also synapse-specific, as glutamate release onto various GABAergic interneurons was not modulated. Importantly, activating L1 NDNF-expressing cells was sufficient to suppress glutamate release from vM1 projections via GABAB receptor-dependent mechanisms. Our research is poised to enhance our understanding of the role of presynaptic inhibition across various types of synapses and its dynamic regulation of synaptic communication. NIH R01NS117636 (SRC) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.