Establishment of precise neuronal connectivity in the neocortex relies on activity-dependent circuit reorganization during postnatal development. In the mouse somatosensory cortex layer 4, barrels are arranged in one-to-one correspondence to whiskers on the face. Thalamocortical axon termini are clustered in the center of each barrel. The layer 4 spiny stellate neurons are located around the barrel edge, extend their dendrites primarily toward the barrel center, and make synapses with thalamocortical axons corresponding to a single whisker. These organized circuits are established during the first postnatal week through activity-dependent refinement processes. However, activity pattern regulating the circuit formation is still elusive. Using two-photon calcium imaging in living neonatal mice, we found that layer 4 neurons within the same barrel fire synchronously in the absence of peripheral stimulation, creating a ''patchwork'' pattern of spontaneous activity corresponding to the barrel map. We also found that disruption of GluN1, an obligatory subunit of the N-methyl-D-aspartate (NMDA) receptor, in a sparse population of layer 4 neurons reduced activity correlation between GluN1 knockout neuron pairs within a barrel. Our results provide evidence for the involvement of layer 4 neuron NMDA receptors in spatial organization of the spontaneous firing activity of layer 4 neurons in the neonatal barrel cortex. In the talk I will introduce our strategy to analyze the role of NMDA receptor-dependent correlated activity in the layer 4 circuit formation.

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides tonic activation of developing interneurons through Grin2D NMDA receptors. Experimental disruption of this pathway results in hyperexcitable cortical circuits and human mutations in the Grin2D gene, as well as other related molecules that regulate early life glutamate signaling, are associated with devastating epileptic encephalopathies. We will explore fundamental mechanisms linking early life glutamate signaling and later circuit hyperexcitability, with an emphasis on potential therapeutic interventions aimed at reducing epilepsy and other neurological dysfunction.