Hippocampal hub neurons maintain distinct connectivity throughout their lifetime

Abstract

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as ‘hubs’ by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during locomotion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.

CA1 pyramidal cell diversity is rooted in the time of neurogenesis

“…The significantly higher E/I ratio received by these cells suggests that they may be preferentially recruited by synaptic excitation, since they are otherwise less intrinsically excitable (lower Rm, low firing rate in response to long depolarizing current injections, lower sag). Interestingly, the same lower excitability (across similar metrics), combined with lower levels of PV inputs was observed in early born CA1 GABAergic neurons and DG granule cells (Bocchio et al, 2020; Gupta et al, 2012; Save et al, 2019), again indicating similar fates in the adult across different subtypes of pioneer neurons.…”

Maximally selective single cell target for circuit control in epilepsy

“…Highly connected but rare hub neurons have been of great interest for studies working towards the goal of advancing seizure control with minimal side-effects 7–9 . This has been motivated by experimental work showing that hub neurons orchestrate network synchrony 12,13 and by computational work predicting their role in the transition from interictal to ictal discharge 11 .…”

“…One conserved feature of complex networks is the presence of richly connected yet sparse hub neurons 10 . It has been shown that these neurons are critical for influencing network dynamics in biological neural circuits 11–13 . Specifically, experimental studies have shown that hub neurons orchestrate network synchrony in the developing brain 12 and maintain their effectiveness in adulthood 13 .…”

“…It has been shown that these neurons are critical for influencing network dynamics in biological neural circuits 11–13 . Specifically, experimental studies have shown that hub neurons orchestrate network synchrony in the developing brain 12 and maintain their effectiveness in adulthood 13 . Simulations in large-scale data-driven hippocampal dentate gyrus computational model of temporal lobe epilepsy (TLE) predicted that perturbation of a population of neurons that included hubs was sufficient to initiate a seizure 11 .…”

Hippocampal Egr1-dependent neuronal ensembles negatively regulate motor learning

“…Hippocampal cell populations are activated during simple locomotion 25 and during a motor learning task 12 . Less clear is whether this activation is cooperative, independent or competitive with the rest of the motor systems such as the striatum or motor cortex 3 .…”