Early Correlated Network Activity in the Hippocampus: Its Putative Role in Shaping Neuronal Circuits

Abstract

Synchronized neuronal activity occurring at different developmental stages in various brain structures represents a hallmark of developmental circuits. This activity, which differs in its specific patterns among animal species may play a crucial role in de novo formation and in shaping neuronal networks. In the rodent hippocampus in vitro, the so-called giant depolarizing potentials (GDPs) constitute a primordial form of neuronal synchrony preceding more organized forms of activity such as oscillations in the theta and gamma frequency range. GDPs are generated at the network level by the interaction of the neurotransmitters glutamate and GABA which, immediately after birth, exert both a depolarizing and excitatory action on their targets. GDPs are triggered by GABAergic interneurons, which in virtue of their extensive axonal branching operate as functional hubs to synchronize large ensembles of cells. Intrinsic bursting activity, driven by a persistent sodium conductance and facilitated by the low expression of Kv7.2 and Kv7.3 channel subunits, responsible for IM, exerts a permissive role in GDP generation. Here, we discuss how GDPs are generated in a probabilistic way when neuronal excitability within a local circuit reaches a certain threshold and how GDP-associated calcium transients act as coincident detectors for enhancing synaptic strength at emerging GABAergic and glutamatergic synapses. We discuss the possible in vivo correlate of this activity. Finally, we debate recent data showing how, in several animal models of neuropsychiatric disorders including autism, a GDPs dysfunction is associated to morphological alterations of neuronal circuits and behavioral deficits reminiscent of those observed in patients.

KCC2-Mediated Cl- Extrusion Modulates Spontaneous Hippocampal Network Events in Perinatal Rats and Mice

“…In agreement with the idea that KCC2 acts to suppress GDP activity, we observed that these events had a higher amplitude in KCC2-null versus wild-type animals, and this difference was closely mimicked by exposure of wild-type mouse hippocampi to the KCC2 blocker VU0463271. Based on our data on KCC2 +/+ versus KCC2 À/À mouse embryos, VU0463271 used at 10 mM shows a high level of specificity, because it does not seem to have off-target effects on the multiple molecular mechanisms that are involved in the generation of GDPs (Ben-Ari et al, 2007;Griguoli and Cherubini, 2017).…”

“…Giant depolarizing potentials (GDPs) are the most pronounced network activity pattern in the perinatal mouse and rat hippocampus (Ben-Ari et al, 1989Sipilä et al, 2005;Spoljaric et al, 2017;Griguoli and Cherubini, 2017). With CA3 as their pacemaker region (Sipilä et al, 2005), GDPs target neighboring areas and propagate along the septo-temporal axis of the developing hippocampus (Leinekugel et al, 1998;Ben-Ari et al, 2007).…”

“…Blankenship and Feller, 2010). GDPs are driven by the intrinsic pacemaker properties of CA3 pyramidal neurons and by the synergistic actions of glutamate and depolarizing GABA (Ben-Ari et al, 1989Sipilä et al, 2005;Khazipov et al, 2015;Griguoli and Cherubini, 2017;Kirmse et al, 2018). The depolarizing GABAergic drive onto pyramidal neurons (Ben-Ari et al, 1989 is brought about by active uptake of Cl À by the Na-K-2Cl cotransporter NKCC1 (Dzhala et al, 2005;Sipilä et al, 2006Sipilä et al, , 2009Spoljaric et al, 2017).…”

Can mutation‐mediated effects occurring early in development cause long‐term seizure susceptibility in genetic generalized epilepsies?

“…Neonatal spindle bursting is an example of an early developmental oscillatory network behavior in rodents that is similar to that seen in humans . Giant depolarizing potentials (GDPs) are localized synchronized events that can be measured in brain slices cut from rodents early in development allowing more detailed molecular mechanisms to be resolved . The coordinated activation of a range of ion channels is critical to the generation of GDPs, with excitatory GABA A receptor transmission a particularly important driver of this activity .…”

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

“…The first model is based on evidence from acute slices suggesting that immature GABA A transmission is capable of driving excitation (Gulledge and Stuart, 2003) and that depolarizing GABA A transmission drives ENOs, which in turn promote glutamatergic synapse formation and unsilencing, and circuit refinement (Hanse et al, 1997; Ben-Ari, 2002; Wang and Kriegstein, 2009; Griguoli and Cherubini, 2017). Disrupting E Cl or GABA A transmission in this phase of development is hypothesized to interfere with synapse formation (S5A Fig), and this has been borne out by experimentally lowering E Cl across the postmitotic period in immature neurons (Ge et al, 2006; Cancedda et al, 2007; Wang and Kriegstein, 2008).…”