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

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 cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.

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

The hippocampus is an elongated brain structure which runs along a ventral-to-dorsal axis in rodents, corresponding to the anterior-to-posterior axis in humans. A glutamatergic cell type in the dentate gyrus (DG), the mossy cells (MCs), establishes extensive excitatory collateral connections with the DG principal cells, the granule cells (GCs), and inhibitory interneurons in both hippocampal hemispheres along the longitudinal axis. Although coupling of two physically separated GC populations via long-axis projecting MCs is instrumental for information processing, the connectivity and synaptic features of MCs along the longitudinal axis are poorly defined. Here, using channelrhodopsin-2 assisted circuit mapping, we showed that MC excitation results in a low synaptic excitation-inhibition (E/I) balance in the intralamellar (local) GCs, but a high synaptic E/I balance in the translamellar (distant) ones. In agreement with the differential E/I balance along the ventrodorsal axis, activation of MCs either enhances or suppresses the local GC response to the cortical input, but primarily promotes the distant GC activation. Moreover, activation of MCs enhances the spike timing precision of the local GCs, but not that of the distant ones. Collectively, these findings suggest that MCs differentially regulate the local and distant GC activity through distinct synaptic mechanisms. KEY POINTS: Hippocampal mossy cell (MC) pathways differentially regulate granule cell (GC) activity along the longitudinal axis. MCs mediate a low excitation-inhibition balance in intralamellar (local) GCs, but a high excitation-inhibition balance in translamellar (distant) GCs. MCs enhance the spiking precision of local GCs, but not distant GCs. MCs either promote or suppress local GC activity, but primarily promote distant GC activation.

Morpho-physiological properties and connectivity of vasoactive intestinal polypeptide-expressing interneurons in the mouse hippocampal dentate gyrus.

The hippocampus is a key brain structure for cognitive and emotional functions. Among the hippocampal subregions, the dentate gyrus (DG) is the first station that receives multimodal sensory information from the cortex. Local-circuit inhibitory GABAergic interneurons (INs) regulate the excitation-inhibition balance in the DG principal neurons (PNs) and therefore are critical for information processing. Similar to PNs, GABAergic INs also receive distinct inhibitory inputs. Among various classes of INs, vasoactive intestinal polypeptide-expressing (VIP+ ) INs preferentially target other INs in several brain regions and thereby directly modulate the GABAergic system. However, the morpho-physiological characteristics and postsynaptic targets of VIP+ INs in the DG are poorly understood. Here, we report that VIP+ INs in the mouse DG are highly heterogeneous based on their morpho-physiological characteristics. In approximately two-thirds of morphologically reconstructed cells, their axons ramify in the hilus. The remaining cells project their axons exclusively to the molecular layer (15%), to both the molecular layer and hilus (10%), or throughout the entire DG layers (8%). Generally, VIP+ INs display variable intrinsic properties and discharge patterns without clear correlation with their morphologies. Finally, VIP+ INs are recruited with a long latency in response to theta-band cortical inputs and preferentially innervate GABAergic INs over glutamatergic PNs. In summary, VIP+ INs in the DG are composed of highly diverse subpopulations and control the DG output via disinhibition.

Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior.

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.