The influence of GABAergic signaling on dendritic processing

GABAergic (?-aminobutyric acid-releasing) signaling plays a crucial role in integration processes of pyramidal neurons. Specific subtypes of GABA releasing interneurons innervate different compartments of pyramidal neurons; thereby modulating the summation of excitatory synaptic input in space and time to generate neuronal output. The intrinsic signaling capabilities of neuronal compartments have been extensively studied and many results about the local processes have been elucidated. However, the functional role of the specific GABAergic innervation in dependence of the location is largely unknown.
At the beginning of my thesis we studied the effects of GABAergic signals on dendritic excitability of layer V pyramidal cells. While hyperpolarization through activation of dendritic GABAA receptors lowered the threshold for dendritic sodium-calcium spikes, somatic hyperpolarization increased the threshold to initiate dendritic spikes. Blockade of low-voltage activated calcium channels abolished the excitatory effect of dendritic GABAA receptors. The results show that specific pattern of GABAergic pyramidal cell innervation can lead to distinct effects on neuronal function, highly dependent on the site of innervation and local intrinsic signaling mechanisms.
Measurements of this study were restricted to somatic whole-cell patch-clamp recordings and its spatial information had to be obtained indirectly. To overcome these limitations we developed a novel approach to record inhibitory postsynaptic potentials by voltage-sensitive dye imaging. Using an improved voltage-imaging technique, the origin and the spread of physiological GABAergic signals as small as 1 mV could be optically resolved from multiple sites in neuronal dendrites. Hence, recordings of specific dendritic GABAergic innervation patterns are able to be performed locally and the GABAergic impact on neuronal integration processes can be evaluated.
Finally, we designed experiments that reveal clearly the shaping effects of GABAA receptor activation of different interneuron classes on subcellular dendritic excitatory postsynaptic potentials. Using voltage-sensitive dye imaging we studied the transmembrane voltage patterns in CA1 pyramidal neurons after Schaffer collateral stimulation. The observed excitation/inhibition ratio showed a high variability degree between different branches of the apical-basal dendritic tree, tending to more inhibitory innervation in the apical dendrite close to the soma. Application of the GABAA receptor antagonist bicuculline revealed an excitatory signal in all dendritic segments studied, indicating that the original patterns were indeed due to inhibitory synaptic transmission. We show that GABAergic inhibition shapes synaptic integration in a dendrite-specific manner, with a large fraction of the dendritic arborization receiving predominantly or exclusively inhibitory signals after stimulation of CA1 inputs.
In summary, my thesis demonstrates that the location of specific GABAergic innervation is of fundamental relevance for neuronal integration processes.