Functional specialization of hippocampal somatostatin-expressing interneurons.

Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single-cell transcriptome analyses have provided a comprehensive Sst-IN subpopulations 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 of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were sufficient to interrupt their firing. In contrast, the Ndnf;;Nkx2-1 intersection identified a population of oriens lacunosum-moleculare 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 hippocampal Sst-INs.

Functional specialization of hippocampal somatostatin-expressing interneurons.

Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single cell transcriptome analyses have provided a comprehensive Sst-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 of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection 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, the Ndnf;;Nkx2-1 intersection 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 hippocampal Sst-INs.

Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity.

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI's pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI's synaptic effects and dampening hyperexcitability.

Brief synaptic inhibition persistently interrupts firing of fast-spiking interneurons.

Neurons perform input-output operations that integrate synaptic inputs with intrinsic electrical properties; these operations are generally constrained by the brevity of synaptic events. Here, we report that sustained firing of CA1 hippocampal fast-spiking parvalbumin-expressing interneurons (PV-INs) can be persistently interrupted for several hundred milliseconds following brief GABAAR-mediated inhibition in vitro and in vivo. A single presynaptic neuron could interrupt PV-IN firing, occasionally with a single action potential (AP), and reliably with AP bursts. Experiments and computational modeling reveal that the persistent interruption of firing maintains neurons in a depolarized, quiescent state through a cell-autonomous mechanism. Interrupted PV-INs are strikingly responsive to Schaffer collateral inputs. The persistent interruption of firing provides a disinhibitory circuit mechanism favoring spike generation in CA1 pyramidal cells. Overall, our results demonstrate that neuronal silencing can far outlast brief synaptic inhibition owing to the well-tuned interplay between neurotransmitter release and postsynaptic membrane dynamics, a phenomenon impacting microcircuit function.