Tonic GABAergic control of mouse dentate granule cells during postnatal development

Abstract

The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABA(A) receptors containing α(5)- and δ-subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus.

Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

“…To do so, we applied NNC-711 (5 M), a specific inhibitor of GABA transporter 1 (GAT-1), to block GABA reuptake (Suzdak et al 1992). Consistent with previous reports in hippocampus (Holter et al 2010;Stell and Mody 2002), NNC-711 shifted I hold to more negative values in six of six cells (⌬I hold ϭ Ϫ19.05 Ϯ 5.96 pA, ⌬CD ϭ Ϫ0.24 Ϯ 0.056 pA/pF; 1-sample t-test, P ϭ 0.0080 vs. baseline; Fig. 1, C and G).…”

Functional role of ambient GABA in refining neuronal circuits early in postnatal development

“…A powerful tonic GABAergic signaling has been described in granule cells of the dentate gyrus already at P3 (Holter et al, 2010). Using subunit-specific pharmacological modulators, it has been demonstrated that, as in adults (Glykys et al, 2008), this conductance is mediated by a5 and d subunits containing extrasynaptic GABA A receptors.…”

“…The relative contribution of receptors containing α5-subunits decreases with age, while that of receptors containing δ-subunits increases, indicating that as in principal cells the expression of d subunits is developmentally regulated. The increased expression of d subunits parallels that of tonic conductance that reaches its maximum during the second postnatal week and then declines (Holter et al, 2010). Surprisingly, unlike immature CA1 and CA3 principal cells (Marchionni et al, 2007), this conductance exerts mainly an inhibitory effect via ashunting inhibition.…”

Role of tonic GABAergic currents during pre- and early postnatal rodent development

“…As discussed above, in particular the different subunit composition of GABA A receptors or distinct distribution and transport modes of GATs can contribute to these age-dependent effects. For instance in the rodent hippocampus α 5 subunit expression (Ramos et al, 2004) and, correspondingly, tonic GABAergic currents (Holter et al, 2010) are up-regulated during the first postnatal week. Due to the depolarizing GABAergic responses during these stages (Ben-Ari et al, 2012), these tonic GABAergic currents increase the excitability of the immature hippocampus (although GABAergic responses can mediate shunting inhibition even at depolarizing potentials; Kolbaev et al, 2011).…”