GABA-Glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep

Abstract

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to fully characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.Significant statementAn increase of theta and gamma power in the dentate gyrus (DG) is an hallmark of paradoxical (REM) sleep (PS) and is suggested to promote learning and memory consolidation by synchronizing hippocampal networks and increasing its outputs to cortical targets. However the neuronal networks involved in such control of DG activity during PS are poorly understood. The present study identifies a population of GABA/Glutamate neurons in the lateral supramammllary nucleus (SuML) innervating the DG that could support such control during PS. Indeed, we show that activation of these SuML-DG projections increase theta power and frequency as well as gamma power in the DG specifically during PS and modulate activity of a subset of DG granule cells.

Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation

“…The segregated localization of neurotransmitter vesicles in the same terminals suggests differential co-transmission of glutamate and GABA at the SuM-DG synapses (Dugué et al, 2005;Somogyi, 2006;Vaaga et al, 2014). Consistent with this observation, SuM terminals in the DG simultaneously release both glutamate and GABA to GCs and GABAergic INs (Billwiller et al, 2020;Hashimotodani et al, 2018;Pedersen et al, 2017). Of note, the ratio of the glutamate-and GABA-mediated components recorded in INs varied from 0.34 to 7.7 (Hashimotodani et al, 2018).…”

“…Single plane coronal sections with bead expression were imaged using a Research High-Class Stereo Microscope System (SZX16, Olympus, Tokyo, Japan). For colocalization analysis of ChR2-eYFP expressing boutons with VGluT2 and VGAT, boutons along ChR2-eYFP expressing axons were identified in zstack images and examined for colocalization and were counted using cell counter plugin in Fiji (a distribution of ImageJ software, NIH, USA, 1.53c) (Billwiller et al, 2020).…”

Selective vulnerability of supragranular layer neurons in schizophrenia

“…Sections from SZ and control cases were processed for simultaneous detection of target mRNAs (CHRFAM7A, CRH, VIP) in combination with calretinin immunohistochemistry as previously described (14, 15). Paraffin embedded sections were first deparaffinized and treated with 3% H2O2 for 10 minutes, rinsed in 0.01M phosphate-buffered saline (PBS, pH 7.4).…”

Hippocampus-retrosplenial cortex interaction is increased during phasic REM and contributes to memory consolidation

“…Furthermore, it was recently shown that PV+ interneurons in the cortex are more active during REM sleep, especially the subset which was active during previous waking periods 29 . These results suggest that theta oscillations within the HPC and the RSC may arise from a similar mechanism dependent on the MS, although many other regions may participate, as for instance the supramammillary nucleus 30 , the mammillary bodies 21 , or the claustrum, whose projections activate the dentate gyrus in the HPC and the RSC during REM sleep 31 . The anterior thalamic nuclei (ATN) are also strong candidates to participate in this network since they are bidirectionally connected with both the HPC and the RSC, show similar theta oscillations, and have been related to the processing of mnemonic spatial information 32 .…”