Excitatory neurons regulate their own inhibition
The neocortex is the most recent evolutionary expansion of the mammalian brain. It is parceled into many areas, controlling different cognitive functions, and 6 layers, containing different types of neuron. The specific function of a region emerges from its connections with other structures and from the organisation of local circuits within that region.
Local circuits mainly comprise excitatory pyramidal neurons (PNs) and inhibitory interneurons (INs). Neocortical PNs can be divided into two main subgroups: commissural (CPNs) and corticofugal PNs (CFuPNs). CPNs are mostly found superficially in layers (L) 2 and 3, and project to the opposite hemisphere, striatum and frontal cortex, whereas CFuPNs are deep (L5/6) and project to subcortical structures. INs expressing the marker parvalbumin (PV) inhibit the activity of both these classes. Intriguingly, PV INs are very selective when choosing which PNs to connect to, and one of the criteria they attend to is which structure the PN sends it connections to. An outstanding question is whether this selectivity is determined by the PN itself, or if PV INs can somehow recognize the different types of PN. Ye et al. (Neuron, 88, 475-483; 2015) now show that PNs can regulate the amount of PV inhibition they receive.
To study this question, the authors “reprogrammed” L2/3 CPNs into CFuPNs, by introducing into L2/3 Fezf2, a gene known to regulate the identity and characteristics of L5 CFuPNs. L2/3 CPNs that were successfully reprogrammed into CFuPNs (iCFuPNs) showed gene expression and electrophysiological properties consistent with L5 CFuPNs rather than L2/3 CPNs. Remarkably, L2/3 iCFuPNs showed increased general inhibitory activity, in line with their L5 relatives, and increased compared to their L2/3 CPN counterparts. The structural correlate of this increase was a higher number of inhibitory fibres arising from PV INs. To confirm this functionally, Ye and colleagues selectively stimulated PV INs and observed levels of inhibition in L2/3 iCFuPNs comparable to L5 CFuPNs, and higher than in L2/3 CPNs.
These results show that genes expressed in PNs can control the amount of inhibition these neurons receive, opening new lines of inquiry on circuit formation and therapeutical approaches for diseases like epilepsy.
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