The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

In violation of Dale’s principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.

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 ...