DYNAMIC CONTROL OF LONG-RANGE AFFERENT INFORMATION BY PRESYNAPTIC GABAB RECEPTOR-MEDIATED INHIBITION IN NEOCORTICAL LAYER 1

The efficacy of synaptic transmission is dynamically and robustly altered by neuromodulators regulating presynaptic release probability. Our understanding of the sources of the neurotransmitters capable of presynaptic modulation and the resulting functional implications at the levels of circuit activity patterns and behavior however remains limited. Our objective is to investigate these unresolved questions within neocortical layer 1 (L1), an important hub for the convergence of brain-wide projections that convey top-down and bottom-up information. Recently, we have identified an interneuron subtype (NDNF⁺ IN) uniquely equipped for mediating GABAergic volume transmission in L1, making these cells ideal candidates for presynaptic control via activation of GABAB receptors (GBRs). Leveraging this, our research employs a multifaceted approach, combining in vitro electrophysiology, GBR pharmacology, optogenetics, in vivo two-photon calcium imaging, and behavioral assays in auditory cortex. Electrophysiological recordings in L1 IN combined with optogenetics, showed that short term plasticity is critically dependent on the presynaptic GBR activation when stimulating long-range projections from somatosensory cortex and zona incerta. Two-photon imaging data reveal that optogenetic activation of NDNF INs suppresses presynaptic calcium signals, consistent with increased extrasynaptic GABA and GBR-mediated inhibition. Notably, our experiments show that the strength of presynaptic modulation depends on both the identity of the presynaptic input and its postsynaptic targets, indicating pathway- and synapse-specific control. Together, these findings identify NDNF INs as a source of presynaptic inhibition in L1 and suggest that GABAergic volume transmission provides a flexible mechanism for selective gating of cortical inputs, with implications for sensory processing and associative learning.