Jan Michael Schulz, University of Basel, Switzerland | Shifting gears: regulation of dendritic electrogenesis and spike output by dendritic inhibition

Bernstein Seminar

When	Jan 15, 2019 from 05:15 PM to 06:00 PM
Where	Lecture Hall, Bernstein Center Freiburg
Contact Name	Ad Aertsen
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Abstract

GABAergic interneurons are highly heterogeneous, forming several functional classes based on their inputs, physiological properties and output targets. The effects of perisomatic inhibition by parvalbumin-positive interneurons is by far the most widely studied form of inhibition. However, recent experimental evidence from opto- and pharmacogenetic studies indicates that specifically GABAergic interneurons that target dendritic compartments powerfully control postsynaptic integration, synaptic plasticity and learning. The mechanisms underlying the efficient GABAergic control of dendritic electrogenesis are not well understood. Using subtype-selective blockers for GABAA receptors (GABAARs) we recently showed that dendrite-targeting somatostatin interneurons and NO-synthase positive neurogliaform cells preferentially activate α5-subunit containing GABAARs (α5-GABAARs), generating slow inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal cells.

By contrast, there was only a negligible contribution of these receptors to perisomatic IPSCs, generated by fast-spiking parvalbumin interneurons. Remarkably, α5-GABAAR-mediated IPSCs were strongly outward-rectifying generating 4-fold larger conductances above -50 mV than at rest. Experiments and modeling showed, that synaptic activation of these receptors can very effectively control voltage-dependent NMDA-receptor activation as well as Schaffer-collateral evoked burst firing in pyramidal cells. In another study, I investigated the regulation of dendritic Ca2+ spikes and somatic action potential output by dendritic GABABR activation using dual somatic and dendritic patch-clamp recordings from neocortical layer 5 pyramidal neurons.

GABABR activation directly inhibited dendritic Ca2+ spikes. In addition, the activation of G-coupled inward rectifying potassium (GIRK) channels in the dendrite resulted in a reduction in the local input resistance and the transfer resistance from dendrite to soma. As both input and transfer resistances are voltage-dependent, this effect became stronger with increasing membrane potential depolarization. Taken together, these results show that dendritic inhibition changes the nonlinear integrative properties of pyramidal neurons and that specialized nonlinear GABAARs with slow kinetics in dendritic synapses mediate powerful control of postsynaptic integration by matching functional properties NMDARs.