Biology subjects

Stern, S.

Publications and source records attributed to Stern, S..

At least 19 recordsLinked to original sources

bioRxiv2026

iPSC-derived extracellular vesicles rescue deficits in human and mouse models of Parkinsons disease

Parkinsons disease (PD) pathogenesis often involves progressive -synuclein (-Syn)-mediated neuronal dysfunction, yet the earliest cellular events that link -Syn pathology to circuit failure remain poorly defined. Here, we used human induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons from patients carrying the familial A53T SNCA mutation to reconstruct a temporal course of dysfunction in vitro. We identified a biphasic trajectory with an early phase of hyperexcitability, characterized by elevated spontaneous firing, followed by a progressive transition into hypoexcitability as the neurons mature, accompanied by reduced network activity, synaptic dysfunction, and -Syn accumulation. Transcriptomic profiling at the critical transition point revealed a dual transcriptional signature, with upregulation of stress-inflammatory pathways (p53, JAK-STAT, apoptosis) coupled with systematic downregulation of metabolic and synaptic maintenance genes. This molecular profile preceded functional collapse, linking early hyperactivity-driven metabolic stress to subsequent neuronal exhaustion. To counteract this pathology, we used extracellular vesicles (EVs), small membrane-bound particles carrying intercellular signals, as a cell-free treatment approach. Strikingly, treatment with EVs derived from healthy iPSCs completely rescued both electrophysiological deficits and pathological -Syn accumulation, restoring normal firing patterns, synaptic function, and network activity. Consistent with these observations, EV treatment reduced -Syn aggregation and improved motor responses in -Syn fibril-injected mice, which are characterized by pathological -Syn accumulation and motor deficits. Overall, these findings demonstrate that EVs derived from healthy iPSCs can reverse PD-related phenotypes in human and mouse models.

neuroscience↗

bioRxiv2026

Baicalin ameliorates behavioral and physiological deficits in Gtf2i-duplication mice and modulates synaptic activity in 7q11.23 Duplication Syndrome patient-derived neurons

7q11.23 Duplication Syndrome (7Dup) is a type of syndromic autism spectrum disorder caused by duplication of a typically 1.5-1.8 Mb segment in section q11.23 of chromosome 7, including 25-27 genes. Previous work has highlighted the GTF2I gene as playing a major role in the phenotype of 7Dup patients. Accordingly, mice with Gtf2i duplication (Gtf2i+/dup) are commonly used as an animal model of 7Dup. We previously reported deficits in several behavioral and physiological modalities, which were associated with Gtf2i dosage in mice conducting a battery of social discrimination tests. Here, we report the effect of treating Gtf2i+/dup mice with Baicalin, a naturally occurring flavonoid added to the mices drinking water (0.15 mg/ml), on these deficits. We found that Baicalin treatment ameliorated the higher surface temperature observed in Gtf2i+/dup males and the lower tail temperature observed in Gtf2i+/dup females during the social behavior tests. It also prevented the increased defecation rate exhibited by Gtf2i+/dup mice during the social preference test. We further analyzed the effect of Baicalin treatment on cortical neurons differentiated from 7Dup patient-derived IPSCs. Using whole cell patch clamp and calcium imaging, we found an increased rate of excitatory postsynaptic currents in Baicalin-treated cells, without a change in their firing rate, indicating a stronger synaptic activity in the Baicalin-treated cells. Altogether, our results reveal that Baicalin administration alleviates some of the behavioral and physiological effects of Gtf2i duplication in mice, and affects neuronal activity in cultured 7Dup human neurons. Thus, Baicalin administration has the potential to serve as a treatment for 7Dup patients.

neuroscience↗

bioRxiv2025

Slowdown of microtubule retrograde flow enables axon and dendrite development and maintenance

Distinct microtubule arrays form in axons and dendrites defining their functions in neurons. These arrays are thought to develop through separate processes. Here we challenge this view by showing that axons and dendrites develop by a unifying process: slowdown of microtubule retrograde flow (MT-RF), a recently discovered mechanism of microtubule dynamics. By integrating quantitative data of microtubule dynamics and distributions into a newly developed biophysical model of microtubules across developmental stages, we uncover that MT-RF interacts with microtubule stability and nucleation. Without MT-RF slowdown, this interaction suppresses development and maintenance of axonal and dendritic microtubule arrays. In axons, MT-RF slowdown enables microtubules to reach the tip, even at long distances, supporting axon growth. In dendrites, late MT-RF slowdown facilitates an efficient increase in stable microtubules. Thus, our data-integrated model reveals MT-RF slowdown as central for the development of distinct neuronal compartments, providing a unifying mechanism for microtubule-related physiology.

neuroscience↗

bioRxiv2025

Behavioral age-detection in individuals reconstructs minute-scale developmental transcriptomics

Capturing rapid changes in gene-expression across development time is crucial for uncovering the molecular pathways that organize dynamic developmental processes. Here, we introduce BehaveSeq, a method that enables time reconstruction of minute-resolution developmental patterns of gene-expression by integrating longitudinal behavioral monitoring for precise age detection with genome-wide transcriptomic profiling in single individuals. By densely sampling individuals every [~]3 minutes during hours of C. elegans development, we uncovered thousands of genes exhibiting rapid and temporally structured expression trajectories. These genes were organized into distinct dynamical patterns associated with specific developmental functions. Moreover, time-reconstruction of transcriptional trajectories in serotonin-deficient individuals revealed time-specific neuromodulatory effects on developmental expression programs. Interestingly, using the same single-animal datasets, we were able to train a neural network model that accurately predicts the developmental age of each individual based on its individual-specific molecular signature. Overall, our method provides a new framework for revealing dynamic gene regulation with high temporal precision across developmental timescales.

developmental biology↗

bioRxiv2025

Divergent Excitability of GABAergic Neurons Derived from Bipolar Disorder Patients Shapes Energy Shifts of Network Dynamics, possibly mimicking mania and depression

Bipolar disorder (BD) is characterized by fluctuating mood states, yet the cellular and circuit-level mechanisms distinguishing lithium-responsive (LR) from non-responsive (NR) patients remain elusive. We derived dentate gyrus granule neurons and GABAergic interneurons from induced pluripotent stem cells (iPSCs) of BD patients stratified by lithium response, and from healthy controls. Using patch-clamp electrophysiology, we assessed intrinsic excitability. We further developed a computational model simulating large-scale neuronal networks based on patient-derived electrophysiological properties and ion channel conductance distributions. Granule neurons from both LR and NR patients exhibited hyperexcitability compared to controls. However, GABAergic neurons showed a striking divergence: LR neurons were hyperexcitable, while NR neurons were hypoexcitable. Transcriptomic profiling revealed distinct molecular signatures between NR and LR neurons, including dysregulation of GABA receptor genes (GABRR1). Computational simulations over 10,000 iterations, mimicking long-term network activity, revealed that dentate granule neuron changes alone failed to recapitulate netwrok shifts between global hyperexcitability and global hypoexcitability. Networks incorporating only granule neuron phenotypes entered persistent hyper- or hypoactive states, depending on lithium response. Remarkably, when GABAergic neuron phenotypes were added to the model, both LR and NR networks exhibited spontaneous transitions between high and low activity states, that may be associated with the mood episodes that the patients exhibit. Control networks did not show such bistability. We, therefore, conclude that GABAergic neuronal excitability is a key determinant of lithium responsiveness in BD and critically shapes the emergence of state-shift dynamics in neural networks. These findings suggest that restoring excitatory/inhibitory (E/I) balance via targeted modulation of interneuron function may offer novel therapeutic avenues for BD.

neuroscience↗

bioRxiv2025

Digestive Dimensions of Autism: A Multiscale Exploration of Gut-Brain Interactions

Social communication difficulties characterize autism spectrum disorders (ASD). Gastrointestinal (GI) symptoms are more common in ASD than in the general population. The identification of GI problems in individuals with ASD is challenging due to their altered pain perception and irregular behaviors. Importantly, GI symptoms and ASD can potentially aggravate each other. However, it is unclear if GI problems cause ASD symptoms or vice versa. A crosstalk between the digestive system, gut microbiota, and the central and enteric nervous systems has been repeatedly reported. The enteric nervous system (ENS) regulates the GI tract with the central nervous system (CNS) and the autonomic nervous system (ANS), as well as independently through specific neural circuits. Several mechanisms contribute to GI problems in ASD, including genetic mutations that affect the enteric nervous system (ENS), dysregulation of the ANS, alterations in gut microbiota, unhealthy dietary preferences, and changes in metabolomic profiles. Furthermore, studies have shown molecular and cellular differences in the GI biopsy of children with and without ASD. These findings highlight the unique nature of GI issues in ASD, underscoring the importance of further investigating the changes that occur in the digestive system and enteric nervous system (ENS) in ASD models.

neuroscience↗

bioRxiv2025

Dysregulation of Multiple Solute Carrier genes and Metabolic Deficits in SLC1A4-Mutant Human iPSC-Derived Hippocampal Neurons

Mutations in SLC1A4, which encodes the neuronal amino acid transporter ASCT1, disrupt metabolic and synaptic homeostasis, contributing to neurodevelopmental deficits commonly observed in autism spectrum disorder (ASD). To investigate the underlying molecular mechanisms of SLC1A4-related disorders, we utilized human iPSC-derived hippocampal neurons and applied an integrated multi-omics approach, combining electrophysiology, calcium imaging, metabolomics, proteomics, and transcriptomics. Our findings reveal an initial phase of early neuronal hyperexcitability, driven by increased sodium and potassium currents, followed by a progressive decline in synaptic activity at later stages. Metabolomic analysis identified elevated glycine, serine, and glutamate levels during early differentiation, contributing to excitotoxicity, whereas later glutamate depletion and extracellular matrix (ECM) disruption were associated with synaptic dysfunction. Proteomics data further showed dysregulation in metabolic pathways, amino acid biosynthesis, and fatty acid metabolism pathways during early time points, and in later stage dysregulation in metabolic and ECM-receptor interactions. Additionally, transcriptomic analysis revealed dysregulation in calcium signaling, amino acid metabolism pathways such as valine, leucine and isoleucine degradation, tryptophan metabolism, and glycine, serine, and threonine metabolism. Further investigation of SLC-family transporter genes uncovered disruptions in glutamate and glycine transport, establishing a direct link between amino acid transport dysfunction and neuronal deficits. Collectively, our study demonstrates that SLC1A4 mutations lead to dysregulation of multiple solute carrier protein genes causing metabolic stress, excitability defects, and synaptic abnormalities, providing a molecular framework for understanding SLC1A4-related neurodevelopmental disorders and identifying potential therapeutic targets.

neuroscience↗

bioRxiv2024

WWOX deficiency impairs neurogenesis and neuronal function in human organoids

WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms. Using neural organoids and single-cell transcriptomics, we identified radial glial cells (RGs) as preferentially affected, with disrupted cell cycle dynamics leading to an accumulation of cells in the G2/M and S phases, overexpression of the proto-oncogene MYC, and concomitant reduction in neuronal generation. Patient-derived organoids exhibited milder phenotypes compared to knockout organoids, showing functional neuronal impairments like hyperexcitability and delayed differentiation rather than RG dysfunction. Remarkably, gene therapy restored neuronal function, normalizing hyperexcitability and promoting maturation, without disturbing RG populations. We propose a model in which WWOX mutations impair neurogenesis via RG through cell-type specific dysregulation of the MYC and Wnt signaling pathways. These insights highlight potential therapeutic strategies for WWOX-related disorders and open avenues for interventions targeting these key molecular pathways. TeaserWWOX mutations disrupt radial glial function and neurogenesis via MYC dysregulation, with gene therapy offering targeted restoration.

neuroscience↗

bioRxiv2024

Neurodegeneration impairs the consolidation of developmentally synchronized behavioral patterns

Animals generate predictable patterns of behavior that are robustly synchronized with the developmental clock. However, the dynamics of the long-term establishment of synchronized behaviors across the entire developmental trajectory, and the neuronal circuits that control this developmental synchronization, remain underexplored. Here, we show that in C. elegans individuals, developmental synchronization of behavior continuously consolidates throughout development time, and that this consolidation is controlled by multiple neuronal pathways. In particular, we found that the degeneration of a specific mechanosensory circuit early in development strongly impairs the developmental synchronization of behavior. Furthermore, early neuronal activity patterns in downstream motor neurons are altered following the mechanosensory circuit degeneration. Interestingly, we show that either pharmacological or genetic neuroprotection of the mechanosensory circuit from degeneration restores normal modes of developmentally synchronized behaviors. These results imply the control of time-locked behaviors across the developmental trajectory by a localized sensory circuit within the nervous system.

neuroscience↗

bioRxiv2024

Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associated Shank3 mutation.

Extracellular vesicles (EVs) are lipid membrane-bound structures that mediate intercellular communication by transferring diverse cargoes, including RNA and proteins. Shank3, a synaptic scaffolding protein critical for synapse structure and function, is implicated in autism spectrum disorder (ASD) and Phelan-McDermid Syndrome (PMS). Early hyperexcitability in cortical neurons is a recognized endophenotype in ASD. Here, we investigated EV-mediated effects in the context of Shank3 deficiency using human iPSC-derived cortical neurons and Shank3B-/- mice. Switching EVs between Shank3 mutant and control neurons revealed that Shank3 mutant-derived EVs transferred the hyperexcitability and accelerated maturation phenotypes to control neurons. This was driven by enriched synaptic proteins (e.g., ACTB, CFL1, AGRN, CLSTN1) in Shank3 mutant-derived EVs as confirmed by proteomic analysis. Conversely, control EVs failed to rescue mutant phenotypes consistent with their lower enrichment for synaptic proteins and related pathways. Further, EVs from mesenchymal stem cells (MSCs) and healthy donor iPSCs, containing synaptic modulators such as complement proteins (C1R, C1S), plasticity-related proteins (MDK, IGFBP3), and homeostatic regulators (FGF2, SFRP1), rescued the hyperexcitability and normalized the maturation in Shank3 mutant neurons. Moreover, intranasal administration of iPSC-derived EVs in Shank3B-/- mice significantly ameliorated ASD-like behavioral deficits, underscoring their therapeutic potential. Together, these findings reveal a novel EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation, addressing a critical unmet need in ASD and related neurodevelopmental disorders treatment.

neuroscience↗

bioRxiv2024

Predicting Suicide Risk in Bipolar Disorder patients from Lymphoblastoid Cell Lines genetic signatures

This research investigates the genetic signatures associated with a high risk of suicide in Bipolar disorder (BD) patients through RNA sequencing analysis of lymphoblastoid cell lines (LCLs). By identifying differentially expressed genes (DEGs) and their enrichment in pathways and disease associations, we uncover insights into the molecular mechanisms underlying suicidal behavior. LCL gene expression analysis reveals significant enrichment in pathways related to primary immunodeficiency, ion channel, and cardiovascular defects. Notably, genes such as LCK, KCNN2, and GRIA1 emerged as pivotal in these pathways, suggesting their potential roles as biomarkers. Machine learning models trained on a subset of the patients and then tested on other patients demonstrate high accuracy in distinguishing low and high-risk of suicide in BD patients. Moreover, the study explores the genetic overlap between suicide-related genes and several psychiatric disorders. This comprehensive approach enhances our understanding of the complex interplay between genetics and suicidal behavior, laying the groundwork for future prevention strategies.

neuroscience↗

bioRxiv2024

Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes

Neurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite diverse etiologies, patients with these disorders may share symptoms. In this study, we aimed to explore potential common mechanisms between seven neurological disorders spanning three categories: neurodegenerative diseases, neuropsychiatric disorders, and neurodevelopmental disorders, by comparing gene expression profiles and focusing on the most prominent dysregulated genes consistently reported within and across disorders. Our results demonstrate 31 genes that are commonly differentially expressed in brain cells and tissues derived from human disease models when compared to healthy controls. These genes were enriched in brain Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, and External encapsulating structure. Remarkedly, dysregulation of ECM genes was evident separately in each of the three categories of disorders. This suggests a notable distinction in the brain ECM in disease states. Furthermore, we identified that the most frequently reported genes among all disorders were GFAP, and IFITM3. Key PointsO_LIAnalysis of 41 human studies revealed 31 significantly dysregulated genes shared among seven neurological disorders when compared to healthy controls, spanning three distinct categories: Neurodegenerative diseases, Neuropsychiatric disorders, and Neurodevelopmental disorders. C_LIO_LIThese shared Differentially Expressed Genes (DEGs) demonstrated significant enrichment for Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, Blood vessel development, and External encapsulating structure. Particularly, SST and BCL6 were the most frequently reported shared DEGs. C_LIO_LINotably, each of the three categories of neurological disorders exhibited significant cellular component enrichment for ECM pathways. C_LIO_LIIn order to distinguish noise genes (false-positive genes) from disease-relevant genes, we identified the DEGs that were reported the highest number of times per disorder. GFAP, followed by IFITM3, were found to be the most reported genes. C_LIO_LIFurthermore, due to partially shared symptoms, we explored commonalities between Autism Spectrum Disorders (ASD) and Schizophrenia. DEGs shared between both disorders were specifically enriched with ECM pathways, External encapsulating structure, Growth factor binding, Cell adhesion molecule binding, and PI3K-Akt signaling pathway. Noteworthy, IFITM2, HSPB1, IFITM3, HSPA1A, MKNK2, GFAP and COL4A1 were among the most frequently reported shared DEGs. C_LIO_LIThe central aspects of our findings suggest a substantial distinction between the Central Nervous System (CNS) ECM in health and disease. C_LI

neuroscience↗

bioRxiv2024

The Effects of Bipolar Disorder Granule Cell Hyperexcitability and Lithium Therapy on Pattern Separation in a Computational Model of the Dentate Gyrus

Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. These abnormalities are normalised after the application of lithium in neurons derived from lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus (DG). We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into DG networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using linear mixed effects modelling. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results agree with a hypothesised relationship between behavioural mnemonic discrimination and DG PS, as previous research has suggested that mnemonic discrimination improves after lithium therapy in lithium responders only. Our work can be expanded on in the future by simulating the effects of lithium-induced neurogenesis on PS.

neuroscience↗

bioRxiv2024

Developmental Regulation of Alternative Polyadenylation in an Adult Stem Cell Lineage

Alternative Cleavage and Polyadenylation (APA) often results in production of mRNA isoforms with either longer or shorter 3UTRs from the same genetic locus, potentially impacting mRNA translation, localization and stability. Developmentally regulated APA can thus make major contributions to cell-type-specific gene expression programs as cells differentiate. During Drosophila spermatogenesis, approximately 500 genes undergo APA when proliferating spermatogonia differentiate into spermatocytes, producing transcripts with shortened 3 UTRs, leading to profound stage-specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that upregulation of PCF11 and Cbc, the two components of Cleavage Factor II (CFII), orchestrates APA during Drosophila spermatogenesis. Knock down of PCF11 or cbc in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Forced overexpression of CFII components in spermatogonia switched cleavage of some transcripts to the proximal site normally used in spermatocytes. Our findings reveal a developmental mechanism where changes in expression of specific cleavage factors can direct cell-type-specific APA at selected genes.

developmental biology↗

bioRxiv2024

Mapping the developmental structure of stereotyped and individual-unique behavioral spaces in C. elegans

Developmental patterns of behavior are variably organized in time and among different individuals. However, long-term behavioral diversity was previously studied using pre-defined behavioral parameters, representing a limited fraction of the full individuality structure. Here, we continuously extracted [~]1.2 billion body postures of [~]2,200 single C. elegans individuals throughout their full development time, to create a complete developmental atlas of stereotyped and individual-unique behavioral spaces. Unsupervised inference of low-dimensional movement modes of each single individual revealed a dynamic developmental trajectory of stereotyped behavioral spaces and exposed unique behavioral trajectories of individuals that deviate from the stereotyped patterns. Moreover, classification of behavioral spaces within tens of neuromodulatory- and environmentally-perturbed populations efficiently uncovered plasticity in the temporal structures of stereotyped behavior and individuality. These results present a comprehensive atlas of continuous behavioral dynamics across development time and a general framework for unsupervised dissection of shared and unique developmental signatures of behavior.

neuroscience↗

bioRxiv2023

The Impact of Electrophysiological Diversity on Pattern Completion in Lithium Nonresponsive Bipolar Disorder: A Computational Modelling Approach

Patients with bipolar disorder (BD) demonstrate episodic memory deficits, which may be hippocampal-dependent and may be attenuated in lithium responders. Induced pluripotent stem-cell derived CA3 pyramidal cell-like neurons show significant hyperexcitability in lithium responsive BD patients, while lithium nonresponders show marked variance in hyperexcitability. We hypothesize that this variable excitability will impair episodic memory recall, as assessed by cued retrieval (pattern completion) within a computational model of the hippocampal CA3. We simulated pattern completion tasks using a computational model of the CA3 with different degrees of pyramidal cell excitability variance. Since pyramidal cell excitability variance naturally leads to a mix of hyperexcitability and hypoexcitability, we also examined what fraction (hyper-vs. hypoexcitable) was predominantly responsible for pattern completion errors in our model. Pyramidal cell excitability variance impaired pattern completion (linear model {beta}=-1.94, SE=0.01, p<0.001). The effect was invariant to the number of patterns stored in the network, as well as general inhibitory tone and pyramidal cell sparsity in the network. Excitability variance, and more specifically hyperexcitability, increased the number of spuriously active neurons, increasing false alarm rates and producing pattern completion deficits. Excessive inhibition also induces pattern completion deficits by limiting the number of correctly active neurons during pattern retrieval. Excitability variance in CA3 pyramidal cell-like neurons observed in lithium nonresponders may predict pattern completion deficits in these patients. These cognitive deficits may not be fully corrected by medications that minimize excitability. Future studies should test our predictions by examining behavioural correlates of pattern completion in lithium responsive and nonresponsive BD patients. Author summaryPatients with bipolar disorder experience debilitating cognitive impairments whose mechanisms are unknown, and these deficits may be greater in patients who do not respond to the mood stabilizer lithium. Studies using induced pluripotent stem cell (iPSC) derived neurons have suggested that CA3 pyramidal cells in lithium nonresponders may have wide diversity of excitability. Our study examines how this diversity of neuronal excitability would impact the computation of pattern completion in the CA3. In a computational model of the CA3, we found that variance in pyramidal cell excitability reliably impaired pattern completion abilities. Furthermore, we found that both the hyperexcitable and hypoexcitable fractions of cells were each responsible for distinct pattern completion errors, depending on the overall level of network inhibition. These results suggest that lithium nonresponsive patients with bipolar disorder will have worse performance on behavioural tasks that are sensitive to pattern completion, potentially including cued recall paradigms. Our results also suggest that mood stabilizers that simply reduce cellular hyperexcitability may not be sufficient to correct micro-circuit level computations in lithium nonresponsive bipolar disorder. Rather, these patients may require development of mood stabilizers that normalize the distribution of neuronal hyperexcitability among CA3 pyramidal cells.

neuroscience↗

bioRxiv2023

Seeking Convergence and Divergence between Autism and Schizophrenia using genomic tools and patients' neurons

Autism spectrum disorders (ASDs) are highly heritable and result in abnormal repetitive behaviors and impairment in communication and cognitive skills. Previous studies have focused on the genetic correlation between ASDs and other neuropsychiatric disorders, but an in-depth understanding of the correlation to other disorders is required. We conducted an extensive meta-analysis of common variants identified in ASDs by genome-wide association studies (GWAS) and compared it to the consensus genes and single nucleotide polymorphisms (SNPs) of Schizophrenia (SCZ). We found approximately 75% of the SNPs that are associated with ASD are also associated with SCZ. We have also probed cellular phenotypes reported in ASD neurons compared to SCZ neurons from induced pluripotent stem cell (iPSC) models. Interestingly, Autism neurons start with an early maturation and schizophrenia neurons start with a late maturation, but both end up with deficits in synaptic activity when compared to control neurons as they mature.

neuroscience↗

bioRxiv2023

Synaptic dysfunction and dysregulation of extracellular matrix-related genes in dopaminergic neurons derived from Parkinson's disease sporadic patients and with GBA1 mutations

Parkinsons disease (PD) is a neurodegenerative disease with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, and gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, sporadic PD (sPD) patients, and PD patients with GBA1 mutations. Our results demonstrate reduced sodium currents and synaptic activity in DA neurons derived from PD patients with GBA1 mutations, suggesting a potential contribution to PD pathophysiology. We also observed distinct electrophysiological alterations in sPD DA neurons that were dependent on the age of disease onset. RNA sequencing analysis revealed unique dysregulated pathways in early and late-onset sPD neurons, further supporting the notion that molecular mechanisms driving PD may be different between PD patients. In agreement with our previous reports, ECM and focal adhesion genes were the top dysregulated pathways in DA neurons from sPD patients and from patients with GBA1 mutations. Overall, this study gives further confirmation that the convergent functional phenotypes of DA neurons derived from PD patients are synaptic abnormalities and at the transcriptome level, ECM and focal adhesion pathways are highly involved in PD pathology across multiple PD-associated mutations as well as sPD.

neuroscience↗