Pioneer glutamatergic cells develop into a morpho-functionally distinct population in the juvenile CA3 hippocampus

Abstract

The developing CA3 hippocampus is comprised by highly connected hub neurons that are particularly effective in achieving network synchronization. Functional hub neurons were shown to be exclusively GABAergic, suggesting that the contribution of glutamatergic neurons to physiological synchronization processes at early postnatal stages is minimal. However, without fast GABAergic transmission, a different situation may prevail. In the adult CA3, blocking fast GABAergic transmission induces the generation of network bursts that can be triggered by the stimulation of single pyramidal neurons. Here we revisit the network function of CA3 glutamatergic neurons from a developmental viewpoint, without fast GABAergic transmission. We uncover a sub-population of early-generated glutamatergic neurons that impacts network dynamics when stimulated in the juvenile hippocampus. Additionally, this population displays characteristic morpho-physiological features in the juvenile and adult hippocampus. Therefore, the apparently homogeneous glutamatergic cell population likely displays a morpho-functional diversity rooted in temporal embryonic origins.

CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus

“…Gene expression in CA3PCs displays prominent laminar specificities 127 , and CA3PC morphological and intrinsic physiological properties vary along the main axes 128,129 , as well as with regard to the extent of mossy fiber innervation of individual CA3PCs 130 . The identification of a subpopulation of early-generated, deep CA3PCs with ability to synchronize adult network activity 110 is consistent with developmentally derived radial differences. Sparse input from granule cells (GCs) to CA3PCs could foster the formation of segregated GC–CA3PC subcircuits through the selective innervation of CA3PCs by GCs born during matched time windows during embryonic 100 and adult 131 neurogenesis.…”

“…Such preferential innervation of clonally related CA1PCs could underlie the observed synchronous activity in sister cells and indicate that the foundations of the biased excitatory–inhibitory local network motifs are at least partly established during development. In agreement with the latter notion, early-born pioneer PCs in the deep CA3PC layer operate as assemblies in the developing hippocampus and later become powerful single units able to influence network dynamics 110 . While developmental programs are likely to play an instructive role in setting up biased connectivity, recent evidence indicates that hippocampal inhibitory circuits undergo a wide range of experience- and learning-related 111–114 plasticity, indicating that biased excitatory–inhibitory microcircuit motifs may be remodeled in vivo 19 .…”

Organization and control of epileptic circuits in temporal lobe epilepsy

“…As predicted, only hub cell activation resulted in large-scale network synchronization, emphasizing the functional importance of these hubs. Mathematical modeling of scale-free networks has shown that hub cells arise early during the growth of a network, and indeed genetic studies have shown that a small group of cells born early in the embryonic stage survive into adulthood and exhibit high levels of connectivity (Marissal et al, 2012; Picardo et al, 2011). Removing hub cells experimentally therefore represents a future possibility for exerting control on an excitable network.…”

Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization

“…Interestingly, when the cells were "fate mapped" via genetic markers to determine the details of their origin, it was discovered that a subpopulation of these distinctively influential cells were born very early during embryonic stages and survived into adulthood (Picardo et al 2011;Marissal et al 2012). These super-connected cells, therefore, seem to play a key role in neural develop-ment and maturation, and they continue to powerfully modulate large-scale network dynamics in the adult brain (Picardo et al 2011;Marissal et al 2012).…”

“…Importantly, it also illustrates that a small population of superconnected neurons are endowed with the capability of influencing and even coordinating the dynamics of remote microcircuits. "Hub" is now a prevailing term to designate such neurons, as they share the common characteristics of high anatomical connectivity and the ability to orchestrate synchronicity of a large population of cells (Bonifazi et al 2009;Picardo et al 2011;Marissal et al 2012;Cossart 2014). In the context of epilepsy, hub cells may be thought of as a "microscopic epileptic focus" or a relatively small group of cells that can control and coordinate microcircuits and recruit larger macrocircuits to lead to generalized seizure activity.…”