Biology subjects

Brenner, K.

Publications and source records attributed to Brenner, K..

4 recordsLinked to original sources

bioRxiv2025

Meta-analysis of the brain transcriptomes of multiple genetic mouse models of schizophrenia highlights dysregulation in striatum and thalamus

Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied brain regions were affected, the striatum and the thalamus emerged as key brain regions of convergence. Striatum showed downregulation of synapse-and oxidative phosphorylation-related gene sets in all models. In the thalamus, mutants separated into two groups based on transcriptomic phenotype: synapse-related gene sets were upregulated in mutants with only schizophrenia and bipolar association, and were downregulated in mutants that are associated with developmental delay/intellectual disability in addition to schizophrenia. Overall, our meta-analysis reveals convergence and divergence in brain transcriptomic phenotype in these schizophrenia genetic models, supports the involvement of striatal disturbance and synapse dysfunction in schizophrenia, and points to a key role of the thalamus.

neuroscience↗

bioRxiv2024

Reduction of SynGAP-γ, disrupted splicing of Agap3, and oligodendrocyte deficits in Srrm2 mice, a genetic model of schizophrenia and neurodevelopmental disorder

Rare loss-of-function variants in SRRM2, which encodes a nuclear speckle scaffold and splicing factor, are associated with schizophrenia and neurodevelopmental disorders. How SRRM2 haploinsufficiency disrupts brain function is unknown. We find that Srrm2+/- mice exhibit (i) large-scale changes in gene expression in neuronal and glial cells, affecting DNA-binding-, synapse-, translation-, mitochondria-related pathways across multiple brain regions; (ii) alterations in splicing and/or abundance of multiple postsynaptic proteins, including reduction of the gamma isoform of SynGAP and elevation of its interactor, Agap3; and (iii) reduced oligodendrocyte proportions, particularly in striatum, accompanied by decreased expression of myelin-related mRNAs and proteins. Human iPSC-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects. Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired startle responses, and EEG recordings reveal reduced sleep spindles resembling humans with schizophrenia. Our findings identify specific synaptic changes, splicing dysregulation, and impaired myelination as mechanisms linking SRRM2 haploinsufficiency to neuropsychiatric disease.

neuroscience↗

bioRxiv2023

Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis

Multiple sclerosis (MS) is considered an inflammatory and neurodegenerative disease of the central nervous system, typically resulting in significant neurological disability that worsens over time. While considerable progress has been made in defining the immune systems role in MS pathophysiology, the contribution of intrinsic CNS-cell dysfunction remains unclear. Here, we generated the largest reported collection of iPSC lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that iPSC-derived cultures from people with primary progressive MS contained fewer oligodendrocytes. Moreover, iPSC-oligodendrocyte lineage cells and astrocytes from people with MS showed increased expression of immune and inflammatory genes that match those of glial cells from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.

neuroscience↗

bioRxiv2022

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations in GRIN2A, encoding a subunit of the NMDA (N-methyl-d-aspartate) receptor, greatly increase the risk of schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that heterozygous Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes, oligodendrocytes); (ii) evidence of reduced activity in prefrontal cortex and increased activity in hippocampus and striatum; (iii) elevated dopamine signaling in striatum; (iv) altered cholesterol biosynthesis in astrocytes; (v) reduction of glutamatergic receptor signalin g proteins in the synapse; (iv) heightened gamma oscillation power in EEG; (vi) aberrant locomotor behavioral pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of schizophrenia, and underscore the utility of Grin2a-deficient mice as a new genetic model of schizophrenia.

neuroscience↗