Biology subjects

Gogos, J. A.

Publications and source records attributed to Gogos, J. A..

8 recordsLinked to original sources

bioRxiv2026

Altered thalamo-prefrontal synchrony dynamics during spatial working memory task performance in a SETD1A loss-of-function mouse model of schizophrenia predisposition

Schizophrenia is associated with profound working memory deficits, for which there are no approved treatments. Rare heterozygous null mutations in SETD1A, a gene encoding a key epigenetic regulatory protein, have been definitively linked to increased risk for schizophrenia and neurodevelopmental disorders. To investigate how SETD1A haploinsufficiency impacts the function of circuits supporting working memory, this study examined neural oscillatory synchrony across a network of brain regions critical for spatial working memory (SWM) in mice carrying a loss-of-function allele in the orthologous SETD1A gene. Local field potential recordings were performed in the prefrontal cortex, dorsal and ventral hippocampus, and thalamic nucleus reuniens in male and female wildtype and Setd1a+/- mice performing a delayed non-match to sample task of SWM. Setd1a+/- mice exhibited unaltered prefrontal-hippocampal neural oscillatory synchrony across frequencies and task epochs. In contrast, Setd1a+/- mice displayed reduced beta-frequency synchrony between the prefrontal cortex and nucleus reuniens during SWM maintenance and blunted bidirectional modulation of prefrontal-reuniens beta- and gamma-frequency synchrony across SWM task epochs. Collectively, this work expands our understanding of how genetic risk for schizophrenia alters functional connectivity within distributed circuits supporting SWM. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/702577v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@8107acorg.highwire.dtl.DTLVardef@11ec407org.highwire.dtl.DTLVardef@d7ce18org.highwire.dtl.DTLVardef@1bb31f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

In vitro reconstitution of hippocampal cell assemblies

Three-dimensional neuronal cultures, such as brain organoids, have proven effective for in vitro modeling of brain development and disease. However, it remains unclear whether these systems can intrinsically generate the spatiotemporal network motifs that support cognitive function, particularly given their lack of sensory input. To address this, we developed a 3D long-range modular neuronal network approach to test whether dissociated embryonic hippocampal cells can self-organize into neuronal manifolds capable of generating network dynamics analogous to the in vivo hippocampal cell assemblies implicated in cognitive function. Using all-optical interrogation, we demonstrate in vitro recapitulation of cell assemblies and their hallmark features, including recurring sequential activation, hierarchical chaining, multi-day stability, resilience to perturbation, and attractor-like pattern completion. We further investigated the effects of acute ketamine exposure on these assemblies, revealing network-wide reconfiguration reminiscent of in vivo responses. Finally, we show that human iPSC-derived neurons can similarly self-organize into modular network architectures. Together, these findings are consistent with an intrinsically "inside-out" view of the brain, rather than a tabula rasa model in which sensory input is required for the emergence of cognitive network motifs, and open new avenues for in vitro modeling of network-level mechanisms relevant to neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Genomic and Transcriptomic Signatures of SETD1A Disruption in Human Excitatory Neuron Development and Psychiatric Disease Risk

Genetic disruption of SETD1A markedly increases the risk for schizophrenia. To elucidate the underlying mechanisms, we generated isogenic organoid models of the developing human cerebral cortex harboring a SETD1A loss-of-function schizophrenia risk mutation. Employing chromatin profiling combined with RNA sequencing, we identified high-confidence SETD1A target genes, analyzed the impact of the mutation on SETD1A binding and transcriptional regulation and validated key findings with orthogonal approaches. Disruption of SETD1A function disturbs the finely tuned temporal gene expression in the excitatory neuron lineage, yielding an aberrant transcriptional program that compromises key regulatory and metabolic pathways essential for neurodevelopmental transitions. Although overall SETD1A binding remains unchanged in mutant neurons, we identified localized alterations in SETD1A binding that correlate with shifts in H3K4me3 levels and gene expression. These changes are enriched at enhancer regions, suggesting that enhancer-regulated genes are especially vulnerable to SETD1A reduction. Notably, target genes with enhancer-bound SETD1A are primarily linked to neuronal functions while those with promoter-bound SETD1A are enriched for basic cellular functions. By mapping the SETD1A binding landscape in excitatory neurons of the human fetal frontal cortex and integrating multimodal neuroimaging and genetic datasets, we demonstrate that the genomic context of SETD1A binding differentially correlates with macroscale brain organization and establish a link between SETD1A-bound enhancers, schizophrenia-associated brain alterations and genetic susceptibility. Our study advances our understanding of the role of SETD1A binding patterns in schizophrenia pathogenesis, offering insights that may guide future therapeutic strategies.

neuroscience↗

bioRxiv2024

Disorganized Inhibitory Dynamics and Functional Connectivity in Hippocampal area CA1 of 22q11.2 Deletion Mutant Mice

Individuals with the 22q11.2 deletion syndrome, one of the strongest genetic risk factors for schizophrenia, demonstrate cognitive impairments, including episodic memory dysfunction. Place cell activity of excitatory pyramidal neurons in the hippocampus supporting episodic memory is impaired in a mouse model for the 22q11.2 deletion (Df(16)A+/-). While excitatory dynamics are under tight inhibitory control by multiple subtypes of GABAergic interneurons, previous studies have predominantly focused on a single subtype of PV-expressing interneurons; there have not yet been studies describing the functional relationships between molecularly identified inhibitory types in Df(16)A+/-mice. Here, we examined interneuron subtype-specific activity dynamics in the dorsal hippocampal area CA1 of Df(16)A+/- mice during random foraging and spatial reward navigation tasks. Capitalizing on 3D acousto-optical deflector two-photon microscopy with post hoc immunohistochemical identification, we found that multiple interneuron types exhibit aberrant responses to reward locations and delayed reward enrichment extinction. Df(16)A+/- inhibitory interneurons also carry markedly reduced spatial information in a subtype-dependent manner. We observed task-dependent changes in the correlation structure and coactivity among multiple GABAergic subtypes, suggesting a broadly disorganized microcircuit functionality in mutant mice. Overall, we identify widespread and heterogeneous subtype-specific alterations in interneuron dynamics during spatial reward navigation, reflecting impaired flexibility and organization in CA1 inhibitory microcircuits. Our study provides critical insights into how schizophrenia-risk mutations affect local-circuit interactions among diverse cell types in the mouse hippocampus during learning and spatial navigation.

neuroscience↗

bioRxiv2023

Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome and schizophrenia

Adults and children afflicted with the 22q11.2 deletion syndrome (22q11.2DS) exhibit cognitive, social, and emotional impairments, and are at significantly heightened risk for schizophrenia (SCZ). The impact of this deletion on early human brain development, however, has remained unclear. Here we harness organoid models of the developing human cerebral cortex, cultivated from subjects with 22q11.2DS and SCZ, as well as unaffected control samples, to identify cell-type-specific developmental abnormalities arising from this genomic lesion. Leveraging single-cell RNA-sequencing in conjunction with experimental validation, we find that the loss of genes within the 22q11.2 locus leads to a delayed development of cortical neurons. This impaired development was reflected in an increased proportion of actively proliferating neural progenitor cells and a reduced fraction of more mature neurons. Furthermore, we identify perturbed molecular imprints linked to neuronal maturation, observe the presence of sparser neurites, and note a blunted amplitude in glutamate-induced Ca2+ transients. The aberrant transcription program underlying impaired development contains molecular signatures significantly enriched in neuropsychiatric genetic liability. MicroRNA profiling and target gene investigation suggest that microRNA dysregulation due to DGCR8 deficiency may drive perturbations of genes governing the pace at which maturation unfolds. Using protein-protein interaction network analysis we define complementary effects stemming from other genes residing within the deleted locus. Our study uncovers reproducible neurodevelopmental and molecular alterations resulting from 22q11.2 deletions, with findings that could advance disease modeling and drive the development of therapeutic interventions.

neuroscience↗

bioRxiv2022

EMC10 reduction in human neurons and adult mouse brain rescues cellular and behavioral deficits linked to 22q11.2 deletion

Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is up-regulation of Emc10, a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here we show that expression and processing of miRNAs is abnormal and EMC10 expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization of Emc10 in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over two months post injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulating EMC10 levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.

neuroscience↗

bioRxiv2020

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

neuroscience↗

bioRxiv2018

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts and mouse brains carrying a 22q11.2-like defect, Df(16)A+/-. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A4 orthologue, dSLC25A4-sesB, affected synapse function and impaired sleep patterns in a neuronal-specific manner. These results identify a novel synaptic role of mitochondrial inner membrane solute transporters. We propose that mitochondria are among key organelles affected by genetic defects that increase the risk of neurodevelopmental disorders.

neuroscience↗