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1. Pluripotent stem cell-derived interneuron progenitors mature and restore memory deficits but do not suppress seizures in the epileptic mouse brain

   https://doi.org/10.1016/j.scr.2018.10.007  

   Anderson, N; Van Zandt, M; Shrestha, S; Lawrence, S; Gupta, J: Chen; Harrsch, F; Boyi, T; Dundes, C; Aaron, G; Naegele, J; et al (January 2018, Stem cell research)

   null (Ed.)

   GABAergic interneuron dysfunction has been implicated in temporal lobe epilepsy (TLE), autism, and schizophrenia. Inhibitory interneuron progenitors transplanted into the hippocampus of rodents with TLE provide varying degrees of seizure suppression. We investigated whether human embryonic stem cell (hESC)-derived interneuron progenitors (hESNPs) could differentiate, correct hippocampal-dependent spatial memory deficits, and suppress seizures in a pilocarpine-induced TLE mouse model. We found that transplanted ventralized hESNPs differentiated into mature GABAergic interneurons and became electrophysiologically active with mature firing patterns. Some mice developed hESNP-derived tumor-like NSC clusters. Mice with transplants showed significant improvement in the Morris water maze test, but transplants did not suppress seizures. The limited effects of the human GABAergic interneuron progenitor grafts may be due to cell type heterogeneity within the transplants. 

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2. Dysregulation of neuropilin-2 expression in inhibitory neurons impairs hippocampal circuit development and enhances risk for autism-related behaviors and seizures

   https://doi.org/10.1038/s41380-024-02839-4  

   Subramanian, Deepak; Eisenberg, Carol; Huang, Andrew; Baek, Jiyeon; Naveed, Haniya; Komatireddy, Samiksha; Shiflett, Michael W; Tran, Tracy S; Santhakumar, Vijayalakshmi (November 2024, Molecular Psychiatry)

   Abstract Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity. 

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3. Connectomic comparison of mouse and human cortex

   https://doi.org/10.1126/science.abo0924  

   Loomba, Sahil; Straehle, Jakob; Gangadharan, Vijayan; Heike, Natalie; Khalifa, Abdelrahman; Motta, Alessandro; Ju, Niansheng; Sievers, Meike; Gempt, Jens; Meyer, Hanno S.; et al (July 2022, Science)

   INTRODUCTION The analysis of the human brain is a central goal of neuroscience, but for methodological reasons, research has focused on model organisms, the mouse in particular. Because substantial homology was found at the level of ion channels, transcriptional programs, and basic neuronal types, a strong similarity of neuronal circuits across species has also been assumed. However, a rigorous test of the configuration of local neuronal circuitry in mouse versus human—in particular, in the gray matter of the cerebral cortex—is missing. The about 1000-fold increase in number of neurons is the most obvious evolutionary change of neuronal network properties from mouse to human. Whether the structure of the local cortical circuitry has changed as well is, however, unclear. Recent data from transcriptomic analyses has indicated an increase in the proportion of inhibitory interneurons from mouse to human. But what the effect of such a change is on the circuit configurations found in the human cerebral cortex is not known. This is, however, of particular interest also to the study of neuropsychiatric disorders because in these, the alteration of inhibitory-to-excitatory synaptic balance has been identified as one possible mechanistic underpinning. RATIONALE We used recent methodological improvements in connectomics to acquire data from one macaque and two human individuals, using biopsies of the temporal, parietal, and frontal cortex. Human tissue was obtained from neurosurgical interventions related to tumor removal, in which access path tissue was harvested that was not primarily affected by the underlying disease. A key concern in the analysis of human patient tissue has been the relation to epilepsy surgery, when the underlying disease has required often year-long treatment with pharmaceuticals, plausibly altering synaptic connectivity. Therefore, the analysis of nonepileptic surgery tissue seemed of particular importance. We also included data from one macaque individual, who was not known to have any brain-related pathology. RESULTS We acquired three-dimensional electron microscopy data from temporal and frontal cortex of human and temporal and parietal cortex of macaque. From these, we obtained connectomic reconstructions and compared these with five connectomes from mouse cortex. On the basis of these data, we were able to determine the effect of the about 2.5-fold expansion of the interneuron pool in macaque and human cortex compared with that of mouse. Contrary to expectation, the inhibitory-to-excitatory synaptic balance on pyramidal neurons in macaque and human cortex was not substantially altered. Rather, the interneuron pool was selectively expanded for bipolar-type interneurons, which prefer the innervation of other interneurons, and which further increased their preference for interneuron innervation from mouse to human. These changes were each multifold, yielding in effect an about 10-fold expanded interneuron-to-interneuron network in the human cortex that is only sparsely present in mouse. The total amount of synaptic input to pyramidal neurons, however, did not change according to the threefold thickening of the cortex; rather, a modest increase from about 12,000 synaptic inputs in mouse to about 15,000 in human was found. CONCLUSION The principal cells of the cerebral cortex, pyramidal neurons, maintain almost constant inhibitory-to-excitatory input balance and total synaptic input across 100 million years of evolutionary divergence, which is particularly noteworthy with the concomitant 1000-fold expansion of the neuronal network size and the 2.5-fold increase of inhibitory interneurons from mouse to human. Rather, the key network change from mouse to human is an expansion of almost an order of magnitude of an interneuron-to-interneuron network that is virtually absent in mouse but constitutes a substantial part of the human cortical network. Whether this new network is primarily created through the expansion of existing neuronal types, or is related to the creation of new interneuron subtypes, requires further study. The discovery of this network component in human cortex encourages detailed analysis of its function in health and disease. Connectomic screening across mammalian species: Comparison of five mouse, two macaque, and two human connectomic datasets from the cerebral cortex. ( A ) Automated reconstructions of all neurons with their cell bodies in the volume shown, using random colors. The analyzed connectomes comprised a total of ~1.6 million synapses. Arrows indicate evolutionary divergence: the last common ancestor between human and mouse, approximately 100 million years ago, and the last common ancestor between human and macaque, about 20 million years ago. ( B ) Illustration of the about 10-fold expansion of the interneuron-to-interneuron network from mouse to human. 

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4. State modulation in spatial networks with three interneuron subtypes

   https://doi.org/10.1126/sciadv.ads9134  

   Parker, Madeline M; Rubin, Jonathan E; Huang, Chengcheng (June 2025, Science Advances)

   Several inhibitory interneuron subtypes have been identified as critical in regulating sensory responses. However, the specific contribution of each interneuron subtype remains uncertain. In this work, we explore the contributions of cell type–specific activity and synaptic connections to the dynamics of a spatially organized spiking neuron network. We find that the firing rates of the somatostatin (SOM) interneurons align closely with the level of network synchrony irrespective of the target of modulatory input. Further analysis reveals that inhibition from SOM to parvalbumin interneurons must be limited to allow gradual transitions from asynchrony to synchrony and that the strength of recurrent excitation onto SOM neurons determines the level of synchrony achievable in the network. Our results are consistent with recent experimental findings on cell type–specific manipulations. Overall, our results highlight common dynamic regimes achieved across modulations of different cell populations and identify SOM cells as the main driver of network synchrony. 

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5. Evolution of Lbx spinal cord expression and function

   Juarez-Morales, J; Weierud, F; England, S; Demby, C; Santos, N; Grieb, G; Mazan, S; Lewis, K (July 2021, Evolution development)

   null (Ed.)

   Ladybird homeobox (Lbx) transcription factors have crucial functions in muscle and nervous system development in many animals. Amniotes have two Lbx genes, but only Lbx1 is expressed in spinal cord. In contrast, teleosts have three lbx genes and we show here that zebrafish lbx1a, lbx1b and lbx2 are expressed by distinct spinal cell types, and that lbx1a is expressed in dI4, dI5 and dI6 interneurons, as in amniotes. Our data examining lbx expression in Scyliorhinus canicula and Xenopus tropicalis suggest that the spinal interneuron expression of zebrafish lbx1a is ancestral, whereas lbx1b has acquired a new expression pattern in spinal cord progenitor cells. lbx2 spinal expression was probably acquired in the ray-finned lineage, as this gene is not expressed in the spinal cords of either amniotes or S. canicula. We also show that the spinal function of zebrafish lbx1a is conserved with mouse Lbx1. In zebrafish lbx1a mutants, there is a reduction in the number of inhibitory spinal interneurons and an increase in the number of excitatory spinal interneurons, similar to mouse Lbx1 mutants. Interestingly, the number of inhibitory spinal interneurons is also reduced in lbx1b mutants, although in this case the number of excitatory interneurons is not increased. lbx1a;lbx1b double mutants have a similar spinal interneuron phenotype to lbx1a single mutants. Taken together these data suggest that lbx1b and lbx1a may be required in succession for correct specification of dI4 and dI6 spinal interneurons, although only lbx1a is required for suppression of excitatory fates in these cells. 

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