EARLY PARVALBUMIN INHIBITION SHAPES THE DEVELOPMENT OF CORTICAL INTERHEMISPHERIC EXCITATORY CONNECTIVITY

The coordinated development of excitatory and inhibitory circuits is essential for the emergence of functional cortical networks. While these systems mature in parallel under genetic and activity-dependent control, how early inhibitory activity shapes long-range excitatory connectivity remains poorly understood. Here, we show that early inhibitory signalling actively sculpts adult interhemispheric connectivity of L2/3 excitatory neurons in the primary somatosensory cortex (S1).
We manipulated distinct components of the cortical inhibitory system during the first two postnatal weeks. Reducing the firing of S1L2/3 excitatory neurons between P5–P11 using inhibitory DREADDs—mimicking enhanced inhibitory drive—increased the number of callosal projection neurons and contralateral axonal innervation in adulthood. Conversely, disrupting GABAergic synapse assembly onto L2/3 neurons by downregulating the postsynaptic scaffold gephyrin markedly reduced the number of adult interhemispheric projection neurons. These bidirectional manipulations indicate that early inhibitory tone prospectively biases pyramidal neuron wiring decisions.
To identify the inhibitory circuit involved, we quantified PV synaptic inputs onto S1L2/3 excitatory neurons and found preferential targeting of callosal versus intrahemispheric projection neurons along development. We then altered PV interneuron activity between P7-P14 using DREADDs. AI-based 3D synaptic reconstructions across thousands of neurons revealed profound reorganization of PV input–output connectivity, including reduced inhibitory output onto L2/3 neurons and diminished thalamocortical input onto PV cells. This synaptic remodelling was associated with a long-term decrease in adult callosal connectivity.
Our findings identify PV-INs as critical gatekeepers during an early developmental window, shaping whether cortical excitatory neurons stabilize long-range interhemispheric projections or integrate into local cortical circuits.