Biology subjects

Valle-Tojeiro, A.

Publications and source records attributed to Valle-Tojeiro, A..

3 recordsLinked to original sources

bioRxiv2025

Epigenetic changes, neuronal dysregulation and metabolomic abnormalities in Zmym2 mutant mice, a genetic model of schizophrenia and neurodevelopmental disorders

Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). ZMYM2 interacts with proteins involved in histone modification and gene regulation, including LSD1 and ADNP; however, its specific roles in the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout of Zmym2 in mice results in widespread disturbances in gene expression affecting diverse molecular pathways, including those related to histone modifications and neuronal activity. Proteomic analysis of synapses reveals dysregulation of lipid metabolism and neurofilament-associated pathways, while metabolomic profiling identifies alterations in sphingomyelin and ceramide levels. Furthermore, Zmym2 mutant mice exhibit abnormal brain oscillation patterns on EEG and locomotor hyperactivity in the open field test. Collectively, these findings underscore the critical role of ZMYM2 in brain development and function and highlight Zmym2 mutant mice as a genetic animal model for SCZ and NDD.

neuroscience↗

bioRxiv2024

Muti-omics characterization reveals brain-wide disruption of synapses and region- and age-specific changes in neurons and glia in Sp4 mutant mice, a genetic model of schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4, a zinc-finger transcription factor, greatly increase risk of schizophrenia and bipolar disorder. To investigate the molecular functions of Sp4 in an unbiased manner in vivo, we performed multi-omics analyses of Sp4 mutant mice. Bulk and single nucleus RNA-seq data showed prominent gene expression changes in all brain regions and most cell types, including neuronal and non-neuronal cells. Gene set enrichment analysis of transcriptomic changes revealed alterations in many molecular pathways, including synapse, oxidative phosphorylation, and ribosome. Synapse proteomics of Sp4 mutants pointed to impaired glutamatergic signaling and altered presynaptic function. In Sp4 heterozygous mutant mice, prefrontal cortex and striatum exhibited downregulation of synapse pathways and neuronal hypoactivity at 1 month, associated with reduced sterol biosynthesis in astrocytes, whereas at 3 months, there was a shift to neuronal hyperactivity, concurrent with suppressed immune pathways in the striatal microglia. Furthermore, our study found that much of the transcriptomic changes might be accounted for by a set of transcription regulators (Nr3c1, Creb1, and Kdm5b) under the control of Sp4. Overall, this study provides cellular and molecular features resulting from Sp4 LoF that may explain the pathophysiology of SCZ-BD psychotic disorder spectrum.

neuroscience↗

bioRxiv2024

Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder

AbstractLoss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates, especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly impacted in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated basal PKA activity in the striatum of Akap11-/- mice, with exaggerated additional response to dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged locomotor response to amphetamine, deficits in associative learning and contextual discrimination, as well as depression-like behaviors. Our study connects molecular changes to circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic disorder.

neuroscience↗