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Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single cell transcriptome analyses have provided a comprehensiveSst-IN subtype census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations ofSst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampalSst-INs that largely tiled the morpho-functional parameter space of theSst-INs superfamily. Notably, theSst;;Tac1intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were both necessary and sufficient to interrupt their firing. In contrast, theNdnf;;Nkx2-1intersection identified a population of oriens lacunosum-moleculare (OLM) INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampalSst-INs.Significance statementGABAergic interneurons are important regulators of neuronal activity. Recent transcriptome analyses have provided a comprehensive classification of interneuron subtypes, but the connections between molecular identities and specific functions are not yet fully understood. Here, we developed an approach to identify and access subpopulations of interneurons based on features predicted by transcriptomic analysis. Functional investigation in transgenic animals revealed that hippocampal somatostatin-expressing interneurons (Sst-INs) can be divided into at least four subfamilies, each with distinct functions. Most importantly, theSst;;Tac1intersection targeted a population of bistratified cells that overwhelmingly targeted fast-spiking interneurons. In contrast, theNdnf;;Nkx2-1intersection revealed a population of oriens lacunosum-moleculare interneurons that selectively targeted CA1 pyramidal cells. Overall, this study reveals that genetically distinct subfamilies ofSst-INs form specialized circuits in the hippocampus with differing functional impact.

BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of theSlc10a4gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4-/-), leads to the accumulation of extracellular dopamine. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain.MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) ofSlc10a4-/-mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT andSlc10a4-/-mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior.ResultsBaseline locomotion during auditory stimulation was similar betweenSlc10a4-/-mice and WT littermates. In WT animals, normal auditory gating was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand,Slc10a4-/-mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment inSlc10a4-/-mice, which was not observed in WT littermates. Prepulse inhibition was also decreased inSlc10a4-/-mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates.ConclusionTheSlc10a4-/-mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest thatSlc10a4-/-mice can be considered as potential models for neuropsychiatric conditions.

In the spinal cord, sensory-motor circuits controlling motor activity are situated in the dorso-ventral interface. The neurons identified by the expression of the transcription factor Doublesex and mab-3 related transcription factor 3 (Dmrt3) have previously been associated with the coordination of locomotion in horses (Equus caballus, Linnaeus, 1758), mice (Mus musculus, Linnaeus, 1758), and zebrafish (Danio rerio, F. Hamilton, 1822). Based on earlier studies, we hypothesized that, in mice, these neurons may be positioned to receive sensory and central inputs to relay processed commands to motor neurons. Thus, we investigated the presynaptic inputs to spinal Dmrt3 neurons using monosynaptic retrograde replication-deficient rabies tracing. The analysis showed that lumbar Dmrt3 neurons receive inputs from intrasegmental neurons, and intersegmental neurons from the cervical, thoracic, and sacral segments. Some of these neurons belong to the excitatory V2a interneurons and to plausible Renshaw cells, defined by the expression of Chx10 and calbindin, respectively. We also found that proprioceptive primary sensory neurons of type Ia2, Ia3, and Ib, defined by the expression of calbindin, calretinin, and Brn3c, respectively, provide presynaptic inputs to spinal Dmrt3 neurons. In addition, we demonstrated that Dmrt3 neurons receive inputs from brain areas involved in motor regulation, including the red nucleus, primary sensory-motor cortex, and pontine nuclei. In conclusion, adult spinal Dmrt3 neurons receive inputs from motor-related brain areas as well as proprioceptive primary sensory neurons and have been shown to connect directly to motor neurons. Dmrt3 neurons are thus positioned to provide sensory-motor control and their connectivity is suggestive of the classical reflex pathways present in the spinal cord.