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 I_M, 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.

Keywords: GABAergic interneurons; GDPs; SPWs; chloride transporters; depolarizing GABA; hippocampus; network-driven events; postnatal development.

Figure 1

Intrinsic bursts exert a permissive role in giant depolarizing potentials (GDPs) generation. On the left: schematic drawing of a pyramidal cell endowed with some of the ionic channels contributing to up- and down regulate intrinsic bursts. Na_p: voltage-dependent sodium channel mediating persistent sodium current (I-Nap); Kv7.2–7.3: potassium channel responsible for I_M; hyperpolarization-activated cyclic nucleotide (HCN)-gated channel mediating I_h; gKCa²⁺: calcium dependent potassium channel mediating the slow after hyperpolarization. In the trace below: whole cell patch clamp recording (in current clamp configuration) from a P3 CA3 principal cell, in the presence of DNQX, APV, PTX to block synaptic transmission. A membrane depolarization from −80 mV to the voltage window where Na_p channels are activated (dashed line) triggers bursting activity (a single burst shown on the right in an expanded time scale). Intrinsic bursts are facilitated by the low expression of I_M. The pacemaking role of I_h in bursting activity is unclear (see text). Calcium rise during repeated action potentials within the burst open calcium-dependent potassium channels responsible for bursts termination. On the right: schematic drawing of the local hippocampal circuit responsible for GDPs. Medial ganglionic eminence (MGE) derived interneurons (gray) give rise to somatostatin (SOM) and parvalbumin (PV)-positive interneurons (blue) innervating the distal and proximal dendrites of pyramidal cells, respectively. CA3 principal cells (green) are connected via recurrent collaterals (red) and through gap junctions. They receive also glutamatergic inputs from entorhinal cortex (EC) and from the controlateral hippocampus (red). At this developmental stage, the majority of GABAergic synaptic contacts on principal cells and interneurons are depolarizing and excitatory (+) because of the outwardly directed flux of chloride ions. Gap junctions favor network synchronization and GDPs occurrence. In addition, GDPs are modulated by extrasynaptic GABA_A and glycine receptors. Activation of GABA_B receptors by massive release of GABA during GDPs, together with the activation of calcium-dependent potassium channels are responsible for GDPs termination. Below: whole cell patch clamp recording (in voltage clamp configuration) of network-driven events (GDPs) from a P5 CA3 principal cell (upper trace) and associated local field potentials (bottom trace). These events are shown on the right in an expanded time scale.

Figure 2

Neuronal circuit involved in sharp wave (SPW) generation in the intact hippocampus. On the right: schematic drawing representing the circuit responsible for SPW generation. On the left: simultaneous extracellular field recordings obtained in vivo (at P6) from stratum pyramidale (upper trace) and stratum radiatum (bottom trace) of CA1 hippocampal area (modified from Leinekugel et al., 2002). In stratum pyramidale the SPW (arrow) is followed by a burst of firing. The largest amplitude of the negative deflection (note the different calibration of the two traces) occurs in the middle of stratum radiatum where CA3 principal cells (green) make synaptic contacts with CA1 neurons (red) through Schaffer collateral and associative commissural (A/C) inputs suggesting, as GDPs, a CA3 origin. The contribution of immature mossy fiber path (dashed line) and perforant path from EC cannot be excluded. All glutamatergic inputs are regulated by local interneurons (blue).