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

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.

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso‐ventral axis is inversely related to the expression levels of plasticity‐related neurotransmitter receptors

“…We think this is unlikely however, because we found that GABA B expression is the highest in the apical dendritic layers of ventral CA1 neurons compared with their dorsal counterparts. Activation of postsynaptic neuronal GABA B receptors (Bettler, Kaupmann, Mosbacher, & Gassmann, ) was shown to directly inhibit several types of voltage‐sensitive calcium channels and generate inhibitory postsynaptic potentials via G protein‐coupled inwardly rectifying K + (GIRK) channels (Chalifoux and Carter, ; Degro, Kulik, Booker, & Vida, ; Liu et al, ; Sun and Wu, ; Yang, Tadavarty, Xu, & Sastry, ). This suggests their greater contribution to a hyperpolarizing action of GABA A receptors, specifically in the VH.…”

Control of E-S Potentiation at two different sites in the dendro-somatic axis

“…It is well 459 known that GABAB transmission is linked to K + conductance, and shows both increases 460 and decreases in conductance. GABAB has been shown to be strongly linked to Kir3 461 activity [24,35], which may be playing a role here. The other candidate that may 462 explain our findings is a change in the cationic HCN channels that contribute to the Ih 463 current.…”

“…This shows the relationship between the dendritic synaptic input current and 341 the amount of that current that reaches the soma, across a range of synaptic responses 342 ( Figure 4B receptor-mediated activity. GABAA receptor density is greatest in the peri-somatic 369 region, while GABAB receptor density is more uniform, but greater in distal dendrites, 370 and highest in the s. radiatum, where Schaffer collateral synapses terminate on CA1 371 pyramidal neurons [16,24,25]. To test the hypothesis that GABAB-mediated 372 transmission was involved in the observed change in D-S coupling after HFS, we 373 examined LTP, E-S coupling, and D-S coupling in the presence of the GABAB receptor 374 antagonist CGP-54626 (CGP).…”

Postsynaptic GABABRs Inhibit L-Type Calcium Channels and Abolish Long-Term Potentiation in Hippocampal Somatostatin Interneurons

“…A subset of recordings were performed in adult rats (9 cells, P50-P60) that confirmed that GABA B Rs minimally activate K + currents in SOM-INs ( Figure S1). Endogenous release of GABA activates only a proportion of the cells' GABA B R complement (L€ uscher et al, 1997;Degro et al, 2015). Therefore, we next measured whole-cell currents (I WC ) produced by the GABA B R agonist baclofen.…”