Barrel cortex development lacks a key stage of hyperconnectivity from deep to superficial layers in a rat model of Absence Epilepsy

Abstract

The development of cortical neuronal wiring is precisely orchestrated and goes through several stages, some of which coincide with critical periods when sensory experience is most influential. In particular, even if ascending excitatory and inhibitory projections from the deep layer 5 to upper layers (1 to 4) are first strong, they recede by the end of the critical period of their targets cells located in upper layers. Although alterations in these transient innervations were shown to impair the construction of the later circuits that will persist into adulthood, it is unknown whether they could lead to pathologies. Here, we address this question in a genetic model of Absence Epilepsy, a neuro-developmental disease, where epileptogenesis occurs during the postnatal maturation of barrel cortex, the seizure initiation site. Using functional mapping by laser scanning photostimulation with glutamate uncaging in slices, we investigated the pattern of projections onto layers 2/3 pyramidal cells from 2-week old rats and found that its maturation skipped the key stage during which pyramidal cells received strong projections from both excitatory and inhibitory neurons located in deeper layers. At the same age, neuron activity recorded in vivo with two-photon functional imaging was organized in fewer clusters than expected during this transient hyper-innervation. Later, around the onset of typical absence seizures (~1 month old), over-excitability of cells was observed across layers. Using this genetic model of childhood epilepsy, we provide first evidence that failure to develop this transient hyper-innervation from deep cortical layers plays a role in pathological neural dysfunctions.

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

“…32 In GAERS rats, this progression towards mature discharges is accompanied by progressively increased excitability of cortical neurons and strengthening of local synaptic activity, 32 increased structural connectivity in the cortex, 33 and altered developmental sequences of cortical wiring. 34 In bilateral SBH rats, the evolution of electrographic patterns likely engage similar mechanisms, and combines intrinsic and circuit excitability changes, modified excitation-inhibition ratio, and altered cortical connectivity, as we demonstrated previously. 25 Because we have observed a slower progression towards fully mature SWDs upon manipulation of excitability of both the SBH, and the normotopic cortex, this suggests that the two regions contribute to the maturation of electrographic patterns.…”