Compartmental distribution of GABAB receptor-mediated currents along the somatodendritic axis of hippocampal principal cells.

Claudius E Degro,Akos Kulik,Sam A Booker,Imre Vida

doi:10.3389/fnsyn.2015.00006

Abstract

Activity of cortical principal cells is controlled by the GABAergic system providing inhibition in a compartmentalized manner along their somatodendritic axis. While GABAAR-mediated inhibitory synaptic transmission has been extensively characterized in hippocampal principal cells, little is known about the distribution of postsynaptic effects of GABABRs. In the present study, we have investigated the functional localization of GABABRs and their effector inwardly rectifying potassium (Kir3) channels by combining electrophysiological recordings in acute rat hippocampal slices, high-resolution immunoelectron microscopic analysis and single cell simulations. Pharmacologically isolated slow inhibitory postsynaptic currents were elicited in the three major hippocampal principal cell types by endogenous GABA released by electrical stimulation, photolysis of caged-GABA, as well as the canonical agonist baclofen, with the highest amplitudes observed in the CA3. Spatially restricted currents were assessed along the axis of principal cells by uncaging GABA in the different hippocampal layers. GABABR-mediated currents were present along the entire somatodendritic axis of principal cells, but non-uniformly distributed: largest currents and the highest conductance densities determined in the simulations were consistently found on the distal apical dendrites. Finally, immunocytochemical localization of GABABRs and Kir3 channels showed that distributions overlap but their densities diverge, particularly on the basal dendrites of pyramidal cells. GABABRs current amplitudes and the conductance densities correlated better with Kir3 density, suggesting a bottlenecking effect defined by the effector channel. These data demonstrate a compartmentalized distribution of the GABABR-Kir3 signaling cascade and suggest differential control of synaptic transmission, dendritic integration and synaptic plasticity at afferent pathways onto hippocampal principal cells.

Highlights

GABAB receptors mediate the slow inhibitory effects of gamma-amino butyric acid (GABA) and contribute crucially to the control of network activity and information processing in cortical circuits by regulating neuronal excitability and synaptic transmission (Kohl and Paulsen, 2010; Palmer et al, 2012; Larkum, 2013)
To assess GABAB receptor (GABABR)-mediated responses produced by synaptic release of GABA, we elicited slow inhibitory postsynaptic current (IPSC) in the presence of AMPA, NMDA, and GABAA receptors antagonists (DNQX, 10 μM; APV, 50 μM and gabazine, 10 μM)
Slow IPSCs were evoked by electrical stimulation to the neuropil surrounding the distal apical dendrites with a single stimulus or trains of five stimuli delivered at 200 Hz (Figure 1A, top)

Summary

Introduction

GABAB receptors mediate the slow inhibitory effects of GABA and contribute crucially to the control of network activity and information processing in cortical circuits by regulating neuronal excitability and synaptic transmission (Kohl and Paulsen, 2010; Palmer et al, 2012; Larkum, 2013). GABABRs preferentially localize to the extrasynaptic membrane and co-cluster with G-protein coupled inwardly rectifying potassium channels (Kir or GIRK) (Kulik et al, 2006). Recent data from the neocortical layer 5 PCs suggest that perisomatic GABABRs activate Kir potassium channels, whereas dendritic GABABRs primarily inhibit voltage-sensitive calcium channels (Breton and Stuart, 2012).

Methods

Results

Conclusion