Biology subjects

Schnell, E.

Publications and source records attributed to Schnell, E..

16 recordsLinked to original sources

bioRxiv2026

Reduced inhibition of hippocampal adult-born granule cells by parvalbumin interneurons after TBI

Traumatic brain injury (TBI) is one of the leading causes of acquired temporal lobe epilepsy. TBI drives hippocampal circuit rearrangements that may contribute to increased seizure risk, such as altered inhibitory circuit function and aberrant post-traumatic neurogenesis. In the hippocampal dentate gyrus, adult-born dentate granule cells (DGCs) acquire inhibitory synaptic inputs from parvalbumin-expressing (PV) interneurons early in their maturation. These inputs are important for circuit integration and feedforward inhibition of these neurons. To test whether DGCs born after TBI have functionally altered PV-mediated innervation, we used genetically modified mice, retroviral vectors, and optogenetics to study adult-born and mature DGCs after TBI. Although DGCs born after TBI acquired inhibitory synaptic inputs during their maturation, PV-mediated inhibition of adult-born DGCs was persistently reduced following TBI. This was not observed in mature granule cells and was not due to TBI-induced changes in PV cell density. This deficit in PV-mediated functional innervation was associated with a transient reduction in release probability at these synapses, which normalized as DGCs matured despite ongoing reduction of functional PV input. Surprisingly, although spontaneous inhibitory postsynaptic currents were reduced for mature granule cells after TBI, these were unchanged in adult-born DGCs. Taken together, these data demonstrate distinct differences in the de novo development and maintenance of PV+ synapses in the dentate gyrus after TBI. The addition of neurons with reduced PV+ interneuron-mediated feed-forward inhibition to the dentate gyrus could contribute to hippocampal hyperexcitability after severe brain injury.

neuroscience↗

bioRxiv2026

α2δ-2 mediates coupling of presynaptic calcium entry to vesicle release in hippocampal parvalbumin-expressing interneurons

The 2{delta} family of auxiliary voltage-gated calcium channel (VGCC) subunits have critical but incompletely understood roles in brain function. Parvalbumin-positive (PV+) interneurons in the hippocampus highly express the 2{delta}-2 isoform, and mice lacking 2{delta}-2 exhibit spontaneous seizures. Thus, we examined PV+ neuron-mediated synaptic inhibition in acutely prepared brain slices from 2{delta}-2 knockout (KO) mice. In the inner molecular layer of the dentate gyrus, 2{delta}-2 KO mice demonstrated an increase in the excitation/inhibition ratio of synaptic inputs onto granule cells. We then used optogenetics to activate PV+ interneurons, which produced dramatically smaller inhibitory synaptic currents in granule cells from 2{delta}-2 KO mice. There was a reduction in PV+ inputs onto granule cells as determined by immunostaining. Functionally, these inputs had a lower probability of GABA release and a decreased readily releasable pool of vesicles compared to littermate controls. VGCC coupling to presynaptic vesicle release was also reduced in dentate gyrus PV+ cells in 2{delta}-2 KO mice, based on manipulations of intracellular and extracellular calcium. Together, our data indicate that 2{delta}-2 plays a critical role in PV+ interneuron-mediated synaptic inhibition, which may contribute to seizures in 2{delta}-2 mutant mice.

neuroscience↗

bioRxiv2026

Hilar mossy cells control structural and functional organization in the dentate gyrus

Hilar mossy cells in the dentate gyrus project widely throughout the hippocampus, broadly contributing to circuit function. Their loss in disease is associated with local functional and structural rearrangements, including retrograde granule cell axon sprouting, aberrant neurogenesis, and disinhibition. To examine how mossy cell loss contributes to these circuit rearrangements, we ablated or silenced hilar mossy cells using viral approaches in transgenic (Crlr-Cre) mice. Both mossy cell ablation and silencing dramatically altered dentate gyrus structure and function, as assessed using immunohistochemical, viral labeling, electrophysiology, and anatomical methods. Both manipulations accelerated the maturation of adult-born neurons, but did not alter neuroblast proliferation or cause granule cell axon sprouting. However, mossy cell ablation, but not silencing, caused collapse of the inner molecular layer accompanied by proximal translocation of middle molecular layer inputs. In both cases, granule cell activity measured by cFos labeling and seizure susceptibility were unchanged after mossy cell loss, indicating functional compensation for the altered network organization. Our results highlight how mossy cells influence dentate gyrus organization and adult neurogenesis but also demonstrate the resilience of the hippocampal circuit to structural or functional perturbations.

neuroscience↗

bioRxiv2026

Biased synaptic activation of dentate granule cells by exercise reflects inputs from the lateral entorhinal cortex.

Hippocampal dentate granule cells receive multisensory information from the entorhinal cortex in a laminated and functionally segregated manner. We previously reported that brief periods of voluntary exercise in mice increased EPSCs and dendritic spines for inputs from the lateral, but not the medial, entorhinal cortex. Here we asked whether laminar specificity was due to molecular changes specific to distal granule cell dendrites or rather was dependent on upstream drive from the entorhinal cortex. Selective chemogenetic stimulation of either lateral entorhinal cortex (LEC) or the medial entorhinal cortex (MEC) increased granule cell dendritic spine density in the selected pathway. However, the preponderance of exercise-activated cells originated from LEC based on expression of an activity-dependent retrograde virus in Fos-TRAP mice. Our results indicate that the preferential activation by exercise reflects the drive of locomotor-related inputs from the lateral entorhinal cortex rather than selective molecular mechanisms in distal dendrites of dentate granule cells. How this activation pattern affects other salient stimuli involving contextual or spatial cues may underlie the benefits of exercise on learning and memory.

neuroscience↗

bioRxiv2024

Distinct functional domains of Dystroglycan regulate inhibitory synapse formation and maintenance in cerebellar Purkinje cells

Dystroglycan is a cell adhesion molecule that localizes to synapses throughout the nervous system. While Dystroglycan is required to maintain inhibitory synapses from cerebellar molecular layer interneurons (MLIs) onto Purkinje cells (PCs) whether initial synaptogenesis during development is dependent on Dystroglycan has not been examined. We show that conditional deletion of Dystroglycan from Purkinje cells prior to synaptogenesis results in impaired MLI:PC synapse formation and function due to reduced presynaptic inputs and abnormal postsynaptic GABAA receptor clustering. Using genetic manipulations that disrupt glycosylation of Dystroglycan or truncate its cytoplasmic domain, we show that Dystroglycans role in synapse function requires both extracellular and intracellular interactions, whereas synapse formation requires only extracellular interactions. Together, these findings provide molecular insight into the mechanism of inhibitory synapse formation and maintenance in cerebellar cortex.

neuroscience↗

bioRxiv2023

Indirect Reciprocity Undermines Indirect Reciprocity Destabilizing Large-Scale Cooperation

Previous models suggest that indirect reciprocity (reputation) can stabilize large-scale human cooperation1. The logic behind these models2-7 and experiments6,8 is that a strategy in which individuals conditionally aid others based on their reputation for engaging in costly cooperative behavior serves as a punishment that incentivizes large-scale cooperation without the second-order free-rider problem. However, these models and experiments fail to account for individuals belonging to multiple groups with reputations that can be in conflict. Here we extend these models such that individuals belong to a smaller, "local" group embedded within a larger, "global" group. This introduces competing strategies for conditionally aiding others based on their cooperative behavior in the local or global group. Our analyses reveal that the reputation for cooperation in the smaller local group can undermine cooperation in the larger global group, even when the theoretical maximum payoffs are higher in the larger global group. This model reveals that indirect reciprocity alone is insufficient for stabilizing large-scale human cooperation because cooperation at one scale can be considered defection at another. These results deepen the puzzle of large-scale human cooperation.

evolutionary biology↗

bioRxiv2023

Altered hippocampal activation in seizure-prone CACNA2D2 knockout mice

The voltage-gated calcium channel subunit 2{delta}-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without 2{delta}-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy in hippocampal tissue from wildtype (WT) and 2{delta}-2 knockout (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos expression within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 hour after handling-associated convulsions, KO mice had fewer c-fos-positive cells in the dentate gyrus, indicating that activity in the dentate gyrus actually decreased. However, the dentate was significantly more active in KO mice compared to WT after administration of a subthreshold pentylenetetrazole dose, consistent with increased susceptibility to proconvulsant stimuli. Other histopathological markers of temporal lobe epilepsy in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar in WT and KO mice, apart from a small but significant increase in hilar mossy cell density, opposite to what is typically found in mice with temporal lobe epilepsy. This suggests that the differences in seizure-associated hippocampal function in the absence of 2{delta}-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset. Significance StatementCalcium channel 2{delta} subunits play important roles in controlling neuronal circuit structure and function, and mutation of the 2{delta}-2 isoform of this protein is associated with spontaneous seizures. In this study, we find that seizures in 2{delta}-2 mutant mice involve altered hippocampal activation without substantial histopathological changes in hippocampal structure. This suggests that the differences in seizure-associated hippocampal function are likely due to altered functional properties of the network as well as to the contribution of additional brain regions to seizures in mice lacking this protein.

neuroscience↗

bioRxiv2023

High quality genome assembly and annotation (v1) of the eukaryotic terrestrial microalga Coccomyxa viridis SAG 216-4

Unicellular green algae of the genus Coccomyxa are recognized for their worldwide distribution and ecological versatility. Most species described to date live in close association with various host species, such as in lichen associations. However, little is known about the molecular mechanisms that drive such symbiotic lifestyles. We generated a high-quality genome assembly for the lichen photobiont Coccomyxa viridis SAG 216-4 (formerly C. mucigena). Using long-read PacBio HiFi and Oxford Nanopore Technologies in combination with chromatin conformation capture (Hi-C) sequencing, we assembled the genome into 21 scaffolds with a total length of 50.9 Mb, an N50 of 2.7 Mb and a BUSCO score of 98.6%. While 19 scaffolds represent full-length nuclear chromosomes, two additional scaffolds represent the mitochondrial and plastid genomes. Transcriptome-guided gene annotation resulted in the identification of 13,557 protein-coding genes, of which 68% have annotated PFAM domains and 962 are predicted to be secreted.

genomics↗

bioRxiv2022

Abnormal CCK/CB1R axon targeting in mouse models of dystroglycanopathy

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+ IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.

neuroscience↗

bioRxiv2021

Adaptive mossy cell circuit plasticity after status epilepticus

Hilar mossy cells control network function in the hippocampus through both direct excitation and di-synaptic inhibition of dentate granule cells (DGCs). Substantial mossy cell loss occurs after epileptic seizures; however the contribution of surviving mossy cells to network activity in the reorganized dentate gyrus is unknown. To examine functional circuit changes after pilocarpine-induced status epilepticus, we optogenetically stimulated mossy cells in acute hippocampal slices. In control mice, activation of mossy cells produced monosynaptic excitatory and di-synaptic GABAergic currents in DGCs. In pilocarpine-treated mice, mossy cell density and excitation of DGCs were reduced in parallel, with only a minimal reduction in feedforward inhibition, enhancing the inhibition:excitation ratio. Surprisingly, mossy cell-driven excitation of parvalbumin-positive basket cells, the primary mediators of feed-forward inhibition, was maintained, indicating increased connectivity between surviving mossy cells and these targets. Our results suggest that mossy cell outputs reorganize following seizures, increasing their net inhibitory effect in the hippocampus.

neuroscience↗

bioRxiv2021

α2δ-2 is Required for Functional Postsynaptic Calcium Channel Nanodomain Signaling

2{delta} proteins (CACNA2D1-4) are required for normal neurological function, although how they control neuronal output remains unclear. Using whole-cell recordings of mouse Purkinje cells, we show 2{delta}-2 is required for functional coupling of postsynaptic voltage-dependent calcium entry with effector mechanisms controlling two different outputs, depolarization-induced suppression of excitation mediated by endocannabinoid signaling, and spike afterhyperpolarization generated by calcium-dependent potassium channels. Our findings indicate an important role for 2{delta}-2 proteins in regulating functional postsynaptic calcium channel-coupling in neurons. Significance StatementCalcium influx via membrane voltage-dependent calcium channels drives numerous neuronal processes by signaling through calcium-dependent effector molecules. Signal precision is achieved in part by calcium channel-effector coupling. In mouse Purkinje cell neurons, we show that neuronal 2{delta}-2 protein functionally couples calcium entry to two different postsynaptic calcium-dependent signals, retrograde endocannabinoid signaling and the action potential afterhyperpolarization. Our findings provide new insights about the control of calcium channel-effector coupling as well as new roles for 2{delta}-2 proteins in neurons.

neuroscience↗

bioRxiv2021

The Size of the Stag Determines the Level of Cooperation

Human societies have expanded from small bands to large nation-states over the past 12,000 years. Yet, how groups scale up cooperation and why cooperation varies widely between societies, remains a central puzzle. We present a theoretical model that addresses these puzzles by extending the classic Stag Hunt game to (a) multiple players, (b) multiple rewards ("stags") of different sizes, and (c) endogenous population growth. This framework reveals a "cooperation ladder" where each rung corresponds to a reward that requires a threshold number of cooperators. As cooperation increases, larger rewards become attainable. Securing a larger reward raises carrying capacity (e.g. by providing more food or energy), enabling subsequent population growth and unlocking the possibility of further cooperative gains. However, between these thresholds, cooperation can stagnate or reverse, effectively incentivizing free-riders at intermediate levels. We show that history matters. Early cooperation and population growth can set groups on divergent, path-dependent trajectories. Our model predicts multiple stable equilibria, with surges in cooperation when a new threshold is within reach, and stalls when higher rewards seem unattainable. This framework helps explain key patterns including why cooperation can sometimes accelerate rapidly, why some societies get stuck at smaller scales, and how seemingly selfish behavior can persist in cooperative groups. Expanding the scale of cooperation may depend on how incentives correspond to both environmental conditions, existing levels of cooperation, and population dynamics, offering a new lens on historical transitions in social complexity and insights for modern coordination challenges such as climate change. Significance StatementSmall groups can sometimes grow into large-scale cooperative societies, while other societies stagnate at smaller scales. Our theoretical model reveals that population growth and cooperative thresholds for accessing resources or energy create a "cooperation ladder." As a groups population increases, new larger-scale payoffs become attainable, which in turn fuels further growth. However, between these critical thresholds, cooperation tends to stall and some free-riding is tolerated. This mechanism offers a new explanation for historical bursts in population and cooperation (such as the agricultural and Industrial revolutions), why some societies remain small, and how selfish behavior can persist in cooperative groups. It also provides insights into global coordination challenges like climate change by highlighting the material conditions needed to sustain and expand large-scale cooperation.

evolutionary biology↗

bioRxiv2019

α2δ-2 protein controls structure and function at the cerebellar climbing fiber synapse

2{delta} proteins (Cacna2d1-4) are auxiliary subunits of voltage-dependent calcium channels that also drive synapse formation and maturation. Because cerebellar Purkinje cells (PCs) only express one isoform of this family, 2{delta}-2 (Cacna2d2), we used PCs as a model system to examine roles of 2{delta} in excitatory synaptic function in a Cacna2d2 knockout mouse. Whole-cell recordings of PCs from acute cerebellar slices revealed altered climbing fiber (CF)-evoked complex spike generation, as well as increased amplitude and faster decay of CF-evoked excitatory postsynaptic currents (EPSCs). CF terminals in the KO were localized more proximally on PC dendrites, as indicated by VGLUT2+ immunoreactive puncta, and computational modeling demonstrated that the increased EPSC amplitude can be partly attributed to the more proximal location of CF terminals. In addition, CFs in KO mice exhibited increased multivesicular transmission, corresponding to greater sustained responses during repetitive stimulation, despite a reduction in the measured probability of release. Electron microscopy demonstrated that mutant CF terminals had twice as many vesicle release sites, providing a morphologic explanation for the enhanced glutamate release. Though KO CFs evoked larger amplitude EPSCs, the charge transfer was the same as wildtype as a result of increased glutamate re-uptake, producing faster decay kinetics. Together, the larger, faster EPSCs in the KO explain the altered complex spike responses, which degrade information transfer from PCs and likely contribute to ataxia in Cacna2d2 KO mice. Our results also illustrate the multidimensional synaptic roles of 2{delta} proteins. Significance Statement2{delta} proteins (Cacna2d1-4) regulate synaptic transmission and synaptogenesis, but co-expression of multiple 2{delta} isoforms has obscured a clear understanding of how various 2{delta} proteins control synaptic function. We focused on roles of the 2{delta}-2 protein (Cacna2d2), whose deletion causes cerebellar ataxia and epilepsy in mice and humans. Because cerebellar Purkinje cells only expresses this single isoform, we studied excitatory climbing fiber synaptic function onto Purkinje cells in Cacna2d2 knockout mice. Using optical and electrophysiological analysis, we provide a detailed description of the changes in Purkinje cells lacking 2{delta}-2, and provide a comprehensive mechanistic explanation for how functional synaptic phenotypes contribute to the altered cerebellar output.

neuroscience↗

bioRxiv2019

Post-ictal neuronal network remodeling and Wnt pathway dysregulation in the intra-hippocampal kainate mouse model of temporal lobe epilepsy

Mouse models of mesial temporal lobe epilepsy recapitulate aspects of human epilepsy, which is characterized by neuronal network remodeling in the hippocampal dentate gyrus. Observational studies suggest that this remodeling is associated with altered Wnt pathway signaling, although this has not been experimentally examined. We used the well-characterized mouse intrahippocampal kainate model of temporal lobe epilepsy to examine associations between post-seizure hippocampal neurogenesis and altered Wnt signaling. Tissue was analyzed using immunohistochemistry and confocal microscopy, and transcriptome analysis was performed on RNA extracted from anatomically micro-dissected dentate gyri. Seizures increased neurogenesis and dendritic arborization of newborn hippocampal dentate granule cells in peri-ictal regions, and decreased neurogenesis in the ictal zone, 2-weeks after kainate injection. Interestingly, administration of the novel canonical Wnt pathway inhibitor XAV939 daily for 2-weeks after kainate injection further increased dendritic arborization in peri-ictal regions after seizure, without an effect on baseline neurogenesis in control animals. Transcriptome analysis of dentate gyri demonstrated significant canonical Wnt gene dysregulation in kainate-injected mice across all regions for Wnt3, 5a and 9a. Intriguingly, certain Wnt genes demonstrated differential patterns of dysregulation between the ictal and peri-ictal zones, most notably Wnt5B, 7B and DKK-1. Together, these results demonstrate regional variation in Wnt pathway dysregulation in the early post-ictal period, and surprisingly, suggest that some Wnt-mediated effects might actually temper aberrant neurogenesis after seizures. The Wnt pathway may therefore provide suitable targets for novel therapies that prevent network remodeling and the development of epileptic foci in high-risk patients.

neuroscience↗

bioRxiv2019

Exercise-induced enhancement of synaptic functiontriggered by the inverse BAR protein, Mtss1L.

Exercise is a potent enhancer of learning and memory, yet we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked mature hippocampal dentate granule cells that were specifically activated during exercise using conditional Fos-TRAP mice. Only a few dentate granule cells were active at baseline, but two hours of voluntary exercise markedly increased the number of activated neurons. Activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity. Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied gene in the adult brain. Overexpression of Mtss1L in neurons increased spine density, leading us to hypothesize that its I-BAR domain initiated membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses. One Sentence SummarySingle episodes of voluntary exercise induced a functional increase in hippocampal synapses mediated by activity-dependent expression of the BAR protein Mtss1L, acting as a novel early effector of synapse formation.

neuroscience↗

bioRxiv2018

Early detonation by sprouted mossy fibers enables aberrant dentate network activity

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an \"early detonation\" mode and an increased probability of release compared to mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release thus facilitating reverberant circuit activity.\n\nSignificance StatementSprouted mossy fibers are one of the hallmark histopathological findings in temporal lobe epilepsy. These fibers form recurrent excitatory synapses onto other dentate granule cells that display profound short-term depression. Here, however, we show that although these sprouted mossy fibers weaken substantially during repetitive activation, their initial high probability of glutamate release can activate reverberant network activity. Furthermore, we find that a lack of tonic adenosine inhibition enables this high probability of release and, consequently, recurrent network activity.

neuroscience↗