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 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.

Functional Neuroanatomy of the Rat Nucleus Incertus–Medial Septum Tract: Implications for the Cell-Specific Control of the Septohippocampal Pathway

“…Most excitatory neurons in the central nervous system appear to express a vesicular transporter for the fast neurotransmitter, glutamate (vGlut1-3), but some glutamatergic neurons also express the vesicular GABA transporter vGAT, an example being a distinct group of neurons in the lateral supramammillary nucleus (SuML) (Soussi et al, 2010), an area critically involved in hippocampal theta rhythm control via direct connections with the septum and hippocampus (Borhegyi et al, 1997;Kiss et al, 2000). The net action of GABA/glutamate co-transmission from SuML to hippocampus was shown to be excitatory (Hashimotodani et al, 2018) and activation of the SuMLhippocampal axis activates dentate gyrus (DG) neurons and increases DG theta and gamma power during paradoxical sleep (Billwiller et al, 2020). The rat NI is directly and reciprocally connected with the medial and lateral parts of the SuM (Goto et al, 2001;Olucha-Bordonau et al, 2003), and similar to the SuM, theta phase-locked neurons were identified in the NI (Kirk and McNaughton, 1991;Ma et al, 2013;Li et al, 2020;Trenk et al, 2022).…”

Granule cells in the infrapyramidal blade of the dentate gyrus are activated during paradoxical (REM) sleep hypersomnia but not during wakefulness: a study using TRAP mice

“…Here we showed that the same SuML neurons are reactivated one week apart during PSR while different GCs are reactivated in the DG. Using optogenetic stimulation of terminals of SuML neurons in the DG, we recently showed that all GCs are both excited and inhibited by the SuML projection 38 . It suggests that although the SuML neurons excite all GCs during PS, other input(s) like the performant path 39 is (are) likely necessary to induce the activation of different GCs over two periods of PSR separated by one week.…”

Excitatory selective LTP of supramammillary glutamatergic/GABAergic cotransmission potentiates dentate granule cell firing

“…With direct connections and indirect connections via the medial septum to the hippocampus, SuM activity is involved in the hippocampal θ rhythm ( 7 , 8 ). Recent studies have indicated that the SuM projection to the DG is related to spatial memory retrieval ( 9 ), sleep and arousal ( 10 – 12 ), and contextual novelty ( 13 ). Despite emerging evidence that the SuM-DG pathway contributes to several brain functions, it remains unknown how the SuM afferents to the DG are involved in brain functions at the cellular, synaptic and circuit levels.…”

“…Recent studies have revealed that the SuM neurons make monosynaptic connections to granule cells (GCs), the DG principal neurons, and corelease glutamate and GABA onto GCs ( 10 , 12 – 15 ). This glutamatergic and GABAergic cotransmission exerts a net excitatory effect on GCs and modulates GC firing through temporal association with entorhinal cortical inputs ( 14 , 15 ).…”