Development of phasic and tonic inhibitory GABAergic currents in mouse dentate gyrus

Abstract

The present thesis describes functional and morphological properties of interneurons and granule cell in developing mouse dentate gyrus, with special focus on inhibitory GABAergic currents. The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at the ‘hippocampal gate’ is important, particularly during postnatal development, when the hippocampal network is prone to seizures. During this critical period of development the intrinsic and synaptic properties of developing inhibitory interneurons were monitored in the molecular layer of mouse hippocampal slices. In this region, mainly calretinin‐positive cells of multipolar appearance were found. These GABAergic interneurons showed maturational changes of their intrinsic and synaptic properties after the first postnatal week. The maturation of molecular layer interneurons went along with faster and larger action potentials, increased repetitive firing, and increased frequency of spontaneous postsynaptic inhibitory currents. All developmental changes in intrinsic and synaptic properties occurred between postnatal day 6‐8 and postnatal day 9‐11, indicating a rapid functional maturation at the end of the first postnatal week. Age‐dependent changes of intrinsic and synaptic properties were also found in developing dentate gyrus granule cells. Similar to interneurons, mature dentate gyrus granule cells exhibited faster and larger action potentials and showed an increased frequency of spontaneous postsynaptic inhibitory currents. Thus, the integration of granule cells in the inhibitory synaptic network of dentate gyrus took place after the second postnatal week. The data shows a rapid functional maturation of intrinsic and synaptic properties of interneurons and granule cells in the dentate gyrus and an early integration into the synaptic networks. However, stratum molecular interneurons were integrated prior to granule cells in the dentate gyrus network, which is corresponding to their subsequent developmental appearance. Besides the influence of phasic synaptic inhibitory currents, throughout postnatal development the dentate gyrus network was also shown to be inhibited by tonic GABAergic currents. In dentate gyrus granule cells, tonic inhibitory currents were mediated by GABAA‐receptors containing α5‐ and δ‐ subunits. These extrasynaptic receptors were activated through the GABA in the extracellular space. The ambient transmitter was delivered by synaptic GABA release and regulated through GABA uptake by the GABA transporter‐1. The contribution of the main components to tonic inhibition was surprisingly stable during granule cell maturation. Throughout postnatal development, tonic inhibition reduced excitability of dentate gyrus granule cells by increasing action potential threshold. It further regulated hippocampal network excitability by preventing overexcitation of the dentate gyrus upon stimulation of entorhinal cortex. Functionally, tonic inhibiton was shown to influence the excitation/inhibition balance of both, the adult and the maturing dentate gyrus.