Differential surface density and modulatory effects of presynaptic GABAB receptors in hippocampal cholecystokinin and parvalbumin basket cells

Abstract

The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in their intrinsic physiological, anatomical and molecular characteristics, but also in their presynaptic modulation of their synaptic output. Most GABAergic terminals are known to contain GABAB receptors (GABABR), but their role in presynaptic inhibition and surface expression have not been comparatively characterized in the two BC types. To address this, we performed whole-cell recordings from CCK and PV BCs and postsynaptic pyramidal cells (PCs), as well as freeze-fracture replica-based quantitative immunogold electron microscopy of their synapses in the rat hippocampal CA1 area. Our results demonstrate that while both CCK and PV BCs contain functional presynaptic GABABRs, their modulatory effects and relative abundance are markedly different at these two synapses: GABA release is dramatically inhibited by the agonist baclofen at CCK BC synapses, whereas a moderate reduction in inhibitory transmission is observed at PV BC synapses. Furthermore, GABABR activation has divergent effects on synaptic dynamics: paired-pulse depression (PPD) is enhanced at CCK BC synapses, but abolished at PV BC synapses. Consistent with the quantitative differences in presynaptic inhibition, virtually all CCK BC terminals were found to contain GABABRs at high densities, but only 40% of PV BC axon terminals contain GABABRs at detectable levels. These findings add to an increasing list of differences between these two interneuron types, with implications for their network functions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-017-1427-x) contains supplementary material, which is available to authorized users.

Differential distribution and function of GABABRs in somato-dendritic and axonal compartments of principal cells and interneurons in cortical circuits

“…In line with these immunocytochemical findings, electrophysiological experiments demonstrated that GABABR activation markedly reduced transmission at CCK BC output synapses, but had an approximately twofold weaker effect at PV BC synapses (Fig. 3A, Booker et al, 2017a). At the output synapse of dendritic-inhibitory CCK and PV IN types, the effect of GABABR activation was more pronounced than at those of BCs with Schaffer collateral associated CCK INs showing the strongest presynaptic inhibitory effect (Fig.…”

“…In general, presynaptic receptors are commonly divided into autoreceptors and heteroreceptors depending on whether they control the release of the cell's own transmitter or act at axon terminals of other cells, respectively. Pre-embedding and SDS-FRL immunoelectron microscopic studies showed consistent labeling for the GABABR subunits in presynaptic compartments of cortical glutamatergic PCs and GABAergic INs (Kulik et al, 2003(Kulik et al, , 2006Vigot et al, 2006;Shaban et al, 2006;Booker et al, 2017a), in boutons of the excitatory granule cells in the dorsal cochlear nucleus (Lujan et al, 2004), as well as in axon terminals of glutamatergic and GABAergic neurons in the visual cortex (Gonchar et al, 2001) and cerebellum (Ige et al, 2000;Kulik et al, 2002). However, the immunoreactivity for the proteins was substantially weaker in axonal than in dendritic compartments.…”

“…At the subcellular level, the immunolabeling for both GABAB1 and GABAB2 was detected in postsynaptic and, to a lesser extent, presynaptic microcompartments of hippocampal PCs (Fig. 1D, Table 1) (Kulik et al, 2003(Kulik et al, , 2006Guetg et al, 2009;Degro et al, 2015) and INs (Booker et al, 2013(Booker et al, , 2017a(Booker et al, , 2017b. In postsynaptic compartments, GABABRs were most abundant at the perisynaptic location (i.e.…”

“…1D) and DG-GCs making asymmetrical excitatory synapses with dendritic spines in the hippocampus (Kulik et al, 2003;Vigot et al, 2006;Guetg et al, 2009), at glutamatergic afferents to amygdala (Shaban et al, 2006), as well as boutons of hippocampal INs targeting the perisomatic domain of neurons in the CA1 area (Table 1, Booker et al, 2013Booker et al, , 2017a. In the hippocampus, quantification of immunoreactivity of GABABRs revealed that in axon terminals of perisomatic-targeting INs showed varied strength of labeling: while CCK boutons had consistently high density, comparable to that of glutamatergic synapses, PV terminals showed a dichotomy with approximately 50% of them containing significantly lower density and the others being negative for GABABRs (Booker et al, 2017a). In line with these immunocytochemical findings, electrophysiological experiments demonstrated that GABABR activation markedly reduced transmission at CCK BC output synapses, but had an approximately twofold weaker effect at PV BC synapses (Fig.…”

N-type calcium channels control GABAergic transmission in brain areas related to fear and anxiety

“…In the hippocampus (HPC), interneurons that express the peptide cholecystokinin (CCK + INs) fully rely on N-type calcium channels to release GABA [12][13][14][15][16]. This is in contrast to interneurons that express somatostatin (SOM) and parvalbumin (PV), which utilize P/Q-type calcium channels to release GABA [13,17,18]. In terminals of pyramidal projection neurons (PNs), N-type calcium channels work together with P/Q-and R-type calcium channels to regulate glutamate release [19][20][21].…”