Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

Abstract

Spatiotemporal interactions between glutamatergic excitatory and GABAergic inhibitory neuronsunderly input-output transformations critical for complex brain functions. However, the extent of malleability in this interplay particularly that occuring via modifications in GABAergic interneuron recruitment and output is relatively unexplored in humans. We demonstrate that a specialized interneuron subtype collectively termed neurogliaform cells embedded in both mouse and human neural circuits are susceptible to remarkably similar activity-dependent modulation in their intrinsic properties including the previously characterized distal axonal phenomenon known as barrage firing. Interestingly, we reveal a parallel yet hitherto undescribed plasticity, occurring in the absence of barrage firing manifesting as an enhanced efficacy of excitatory depolarizing inputs to somatodendritic domains in eliciting action potential output. In principle, these evolutionary conserved plasticity routes tune the extent of inhibition mediated by neurogliaform cells constituting circuit mechanisms relevant for human cognitive processing and behavior.only in rodents but also in non-human primates and humans revealing both similar and divergent properties across these species 17,24,30, 36, 37 . However, only a few reports have described short and longterm plasticity impacting recruitment and activity of mouse NGFCs 38, 39 with a conspicuous lack of published evidence demonstrating any such mechanisms in their human counterparts 15 .In the current study we demonstrate that adult mouse and human NGFCs can undergo analogous forms of activity-dependent modulation of their intrinsic properties. In particular, we reveal a previously undescribed plasticity manifesting as a short-term enhancement in the ability of depolarizing inputs to evoke action potential output which, in mouse, is in part due to functional regulation of subthreshold, transient K + -conductance(s) (including those mediated by Kv4-containing channels).Although the underlying induction and expression mechanisms remain to be fully determined, this evolutionary retention demonstrates that the ability to modulate NGFC excitability represents canonical mechanisms stressing their importance. From a research perspective, this conservation also highlights the relevance of the mouse model as a predictive tool in basic science research aimed at further unravelling the behavioral correlates dependent on the tuning of NGFC mediated inhibition 40 under physiological and pathological contexts in humans. RESULTS Activity-dependent enhancement in intrinsic excitability of NGFCs manifested by barrage firing is evolutionary conserved.EGFP+ interneurons (INs) with soma located in the superficial portion of stratum lacunosummoleculare (SLM) of mid-ventral hippocampi and Layer I (LI) of cortex (lateral to mid-ventral hippocampi) interneurons in P35-P60 GAD65-EGFP or Htr3A-EGFP mice were targeted 41, 42, 43 . Using the approach outlined above our data was restricted to NGFCs derived from progenitors ...

The ins and outs of inhibitory synaptic plasticity: Neuron types, molecular mechanisms and functional roles

“…PV + BCs show remarkable high action potential frequency (>10 Hz; Sik et al., 1995), whereas hippocampal NGFCs fire maximally up to 10 Hz during theta network oscillations in vivo (Fuentealba et al., 2010) under basal conditions without applying any stimulation. Neocortical and hippocampal NGFCs also display a so‐called barrage firing (Chittajallu et al., 2020; Sheffield, Best, Mensh, Kath, & Spruston, 2011; Suzuki, Tang, & Bekkers, 2014), a persistent spiking activity occurring up to several minutes after cells’ stimulation, which can reach frequencies up to 130 Hz. Because of prominent frequency‐dependent synaptic depression, it is still unclear how much inhibition is provided to postsynaptic targets during NGFC barrage firing.…”

Synaptic and intrinsic potentiation in O-LM interneurons is induced by theta patterns of stimulation

“…LTP-IE in parvalbumin positive basket cells is mediated by synaptic stimulation of mGluR5 induced by high frequency stimulation of glutamatergic inputs and the down-regulation of Kv1 channels (Campanac et al, 2013). Long-lasting increase in excitability of neurogliaform interneurons is induced by action potential firing at 30 Hz and mediated by the regulation of Kv4 channels (Chittajallu et al, 2020). LTD-IE in O-LM cells is induced by negative pairing of single spike with EPSP at 10 Hz and requires the eCB-mediated up-regulation of Kv7 channels (Incontro et al, 2021).…”

“…Activity-dependent changes in intrinsic excitability have been reported in only a few type of hippocampal interneurons including basket cells (Campanac et al, 2013), GABAergic interneuron-targeting neurogliaform interneurons (Chittajallu et al, 2020) and O-LM interneurons (Incontro et al, 2021). Intrinsic plasticity is induced by glutamatergic synaptic stimulation or electrical stimulation and requires the regulation of inhibitory ion channels.…”

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

“…The Pafah1b1 +/+ and Pafah1b1 +/- datasets were first merged with the Allen Institute reference and in-house MGE interneuron reference datasets. To analyze the Allen Institute mouse dataset of the single-cell transcriptomes of ~76,000 cells from >20 areas of mouse cortex and hippocampus, we downloaded the transcriptome/HDF5 file ( https://portal.brain-map.org/atlases-and-data/rnaseq ) and subsequently converted into Seurat v3-compatible format based on the instructions provided in the Allen Institute Portal ( https://portal.brain-map.org/atlases-and-data/rnaseq/protocols-mouse-cortex-and-hippocampus ) and custom scripts in R package as previously described ( Chittajallu et al, 2020 ). Single-cell transcriptomes from Nkx2.1 -cre:Ai14, MGE-derived cortical and hippocampal interneurons (postnatal day 18–20) were processed as previously described ( Mahadevan and Mitra, 2020 ).…”