Postnatal GABAergic function shapes cortical connectivity from default interhemispheric wiring to specialized local circuits

Abstract

Neocortical circuits of the mammalian brain are responsible for sensory integration and elaboration of complex behaviors. Perception and adaptation to a fluctuating environment are fundamental not only for survival but also for social interactions. Within these networks, the corpus callosum (CC) connects both brain hemispheres and mediates the bilateral integration required for the higher-order functions. The hierarchical organization of neuronal circuits emerges during development and relies on the coordinated action of two major neuronal classes: glutamatergic excitatory projection neurons (PNs) and GABAergic inhibitory interneurons (INs). PNs, including callosal projection neurons (CPNs), receive early inputs from INs. However, whether GABAergic synapses influence the wiring of differentiating PNs is unknown. Recent data revealed that, in normal development, most PNs in layers (L) 2/3 and 4 initially project interhemispherically, with adult CC connectivity emerging after activity-dependent refinement or stabilization of callosal axons. Using pharmacological and genetic approaches, we found that GABAergic modulation controls the integration of PNs into the local or callosal circuit. By administering the GABAA receptor agonist diazepam, we revealed an early postnatal window of plasticity to rewire L4 PNs of the primary somatosensory cortex (S1), shifting from the canonical local projection pattern to callosal connectivity. Such rewiring was preceded by a reduced synaptic integration of S1L4 PNs in the nascent intracolumnar excitatory circuit. Moreover, diazepam treatment in sensory-deprived mice –with defective L2/3 CPN and GABAergic connectivity– recovered L2/3 CPN number to physiological levels. Together, these findings revealed the crucial role of GABA signaling during precise temporal windows to shape upper layer CC circuits. Interneurons comprise a heterogeneous group of cells serving as the primary source of GABA. To dissect whether specific IN subtypes act as physiological modulators of PNs wiring, we separately ablated the two major GABAergic subpopulations: the early-functional somatostatin (SST) INs and the late-maturing parvalbumin (PV) INs. Deletion of SST INs –but not PV INs– reduced the synaptic integration of S1L4 PNs into local assemblies and promoted their stabilization as interhemispheric neurons, reproducing the effect of the diazepam treatment. SST-ablated animals also displayed a paradoxical increase in cortical inhibition at P6 likely produced by a premature PV synaptogenesis onto S1L4 neurons. Our data demonstrate that decreased excitatory transmission or enhanced inhibition at early stages of S1L4 PN differentiation promotes L4 CPN wiring. During normal development, an S1-specific SST-PV motif, likely orchestrated by the thalamus, restricts the early onset of inhibition onto S1L4 PNs and cancels their prospective CPN wiring, thereby selecting S1L4 PNs local connectivity