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.
Highlights
During brain development, neuronal circuits established by a fixed genetic program, regulated already in utero by maternal factors, undergo refinement though adaptive processes involving experience- or activity-dependent mechanisms such as synapse formation and elimination (Ben-Ari, 2001; Spitzer, 2006)
giant depolarizing potentials (GDPs) are generated by the interplay between the neurotransmitters GABA and glutamate that, early in postnatal life, are both depolarizing and excitatory (Ben-Ari et al, 1989)
Additional factors that may contribute to trigger GDPs in the immature hippocampus are: (i) the low expression of Kv7.2 and Kv7.3 channels, responsible for the non-inactivating, low-threshold M current (IM) that in adulthood controls spike after-depolarization and burst generation (Yue and Yaari, 2004); (ii) the slow activating inwardly rectifying cationic current Ih mediated by HCN channels highly expressed in the hippocampus from birth, known to facilitate network oscillations (Pape, 1996)
Summary
Neuronal circuits established by a fixed genetic program, regulated already in utero by maternal factors (see Reid et al, 2017), undergo refinement though adaptive processes involving experience- or activity-dependent mechanisms such as synapse formation and elimination (Ben-Ari, 2001; Spitzer, 2006). The activation of high affinity extrasynaptic GABAA receptors by ambient GABA generates a tonic GABAA-mediated conductance that contributes to depolarize targeted cells to the voltage window where intrinsic bursts are generated (Sipilä et al, 2005, 2009), and to enhance the glutamatergic drive to principal cells (Marchionni et al, 2007).
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