Abstract
Dendrite-targeting GABAergic interneurons powerfully control postsynaptic integration, synaptic plasticity, and learning. However, the mechanisms underlying the efficient GABAergic control of dendritic electrogenesis are not well understood. Using subtype-selective blockers for GABAA receptors, we show that dendrite-targeting somatostatin interneurons and NO-synthase-positive neurogliaform cells preferentially activate α5-subunit- containing GABAA receptors (α5-GABAARs), generating slow inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal cells. By contrast, only negligible contribution of these receptors could be found in 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 show 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. Taken together, nonlinear-rectifying α5-GABAARs with slow kinetics match functional NMDA-receptor properties and thereby mediate powerful control of dendritic postsynaptic integration and action potential firing by dendrite-targeting interneurons.
Highlights
Dendrite-targeting GABAergic interneurons powerfully control postsynaptic integration, synaptic plasticity, and learning
Taking advantage of targeted optogenetic stimulation of different CA1 interneuron subtypes in combination with the highly selective α5-NAM RO4938581, we found that SOM and NOS interneurons targeting distal CA1-pyramidal-cell dendrites in stratum lacunosum moleculare (SLM) preferentially activate α5-GABAA receptors (GABAARs) which contribute 50–80% to the peak conductance
We have found that synaptic α5-GABAARs preferentially control NMDA-receptor-mediated synaptic depolarization, while nonα5-receptors affect NMDA- and non-NMDA-PSPs to a similar extent
Summary
Dendrite-targeting GABAergic interneurons powerfully control postsynaptic integration, synaptic plasticity, and learning. Nonlinear-rectifying α5-GABAARs with slow kinetics match functional NMDA-receptor properties and thereby mediate powerful control of dendritic postsynaptic integration and action potential firing by dendrite-targeting interneurons. By contrast, silencing of dendrite-targeting SOM interneurons strongly increases NMDAR-dependent burst firing in pyramidal cells[6,7] This indicates that dendrite-targeting interneurons can more powerfully control NMDAR activation and synaptic plasticity than PV interneurons. In contrast to PV interneurons, SOM cells generate smallamplitude IPSCs17 It is largely unclear how dendritic GABAergic synapses exert their powerful control of dendritic NMDAR activation and burst firing. Using interneuron-specific genetic mouse lines and Credependent ChrR2 expression, we studied kinetic properties and subunit composition of synaptic GABAA receptors (GABAARs) activated by SOM interneurons and NO-synthase (NOS)expressing neurogliaform cells, targeting distal dendrites of CA1 pyramidal cells. Ultrastructural data suggested a specific enrichment in the postsynaptic membrane of hippocampal and neocortical pyramidal cells[23]
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