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

Abstract

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs).Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses.Collectively, these findings provide physiological significance of the co-transmission of glutamate/GABA by SuM neurons in the DG network.

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

“…This more targeted form of inhibition ( 66 ) than the typical disynaptic feedforward inhibition, which could be spatially isolated from excitatory inputs, may exclude the possibility that the action of GABAergic cotransmission of SuM inputs is depolarizing ( 60 , 63 ). However, it should be noted that SuM neurons also excite dentate INs, driving feedforward inhibition to GCs ( 14 , 15 ). Therefore, we cannot exclude the possibility that GABAergic inputs derived from feedforward inhibition recruited by SuM inputs contribute to regulation of GC firing.…”

“…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 ).…”

“…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 ). Similar corelease of glutamate and GABA from the same presynaptic terminals in the mature brain has been reported in the lateral habenula from the entopeduncular nucleus ( 16 – 19 ) and the ventral tegmental area inputs ( 18 , 20 , 21 ), in the ventral tegmental area from the ventral pallidum inputs ( 21 ), and in the CA1 pyramidal cells from subsets of hippocampal interneurons (INs) ( 22 , 23 ).…”

Connectivity and synaptic features of hilar mossy cells and their effects on granule cell activity along the hippocampal longitudinal axis

“…We chose these two specific intervals to investigate the effects of excitatory postsynaptic conductance (EPSG) and inhibitory postsynaptic conductance (IPSG) selectively on action potential generation. The fast‐spiking phenotype of hippocampal INs or putative soma‐targeting INs recorded at room temperature (21–24°C) were defined by their maximal firing rate >65 Hz and coefficient of variation <0.2 in response to a 1 s depolarizing current injection (Ajibola et al., 2021; Lien & Jonas, 2003). Recordings were made with Multiclamp 700B amplifiers (Molecular Devices), low‐pass filtered at 4 kHz and digitized at 10 kHz (Digidata 1440A, Molecular Devices), and controlled by pCLAMP 10.3 software (Molecular Devices).…”

“…GluA2/3‐, PV‐, or SST‐immunoreactive cells were identified in z‐ stack images and examined for colocalization with ChR2‐eYFP‐expressing cells. The co‐labelled cells were counted using the counter plugin in Fiji (a distribution of ImageJ software, NIH, Bethesda, MD, USA, 1.53c; Ajibola et al., 2021; Schindelin et al., 2012).…”