Interaction of GABAA-receptor function and network activity in the developing hippocampus
Synchronized oscillatory network activity represents a characteristic feature of the developing telencephalon and is believed to be essential for the morphological and functional maturation of immature neuronal circuits. In the hippocampus, the main representatives of synchronized network activity during early brain development are giant depolarizing potentials (GDPs) in vitro and sharp waves as their most probable in vivo counterparts. The generation of these activity patterns is strongly promoted by GABAAR activation which, at this time, is mainly depolarizing and mediates postsynaptic excitation. We hypothesize a reciprocal interaction of GABAA-receptor (GABAAR) function and this form of early network activity. We suggest that I) the proper maturation of synaptic and extrasynaptic GABAAR function is highly activity-dependent and, at the same time, II) GABAAR-mediated postsynaptic currents are governing early network activity.
To elucidate the interactions between GABAAR-mediated transmission and network activity we will manipulate GABAergic transmission both pre- and postsynaptically. Firstly, we will use a transgenic mouse line with a cell-type specific disruption of the chloride co-transporter NKCC1 to attenuate GABAergic depolarization in excitatory neurons, leaving presynaptic GABAergic cells unaffected. Secondly, we intend to disrupt GABA release by deleting the vesicular GABA transporter in a cell-type specific manner using cre-loxP technology. We will apply fast confocal and 3-dimensional 2-photon calcium imaging to record hippocampal neuronal network activity during the first postnatal week in acute slices in vitro and the intact hippocampus in vivo at single-cell resolution.
To achieve a cell-type specific readout of neuronal activity, calcium imaging with a synthetic indicator dye will be performed in mice expressing the fluorescent reporter tdTomato under the Emx1 promoter which allows differentiation between glutamatergic and GABAergic neurons. Alternatively, cell-type specific cre-driver lines will be used to induce expression of the genetically-encoded calcium indicator GCaMP3. All animal models with manipulations of early network activity will be analyzed for changes in GABAAR function using electrophysiological means, including analysis of pre- and postsynaptic parameters of synaptic strength, postsynaptic GABAAR properties as well as tonic GABAAR conductances. Recording from both genetically manipulated and unaffected cells in the same preparation will allow us to dissect cell-autonomous from network-driven mechanisms.
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