Biology subjects

Picard, I.

Publications and source records attributed to Picard, I..

3 recordsLinked to original sources

bioRxiv2025

Spatially resolved translational dysregulation in Grin2a+/- mouse model of schizophrenia

Loss-of-function (LoF) mutations of GRIN2A, encoding the GluN2A subunit of N-methyl-D-aspartate receptor (NMDAR), confer a high risk for schizophrenia (SCZ)1-3, yet how they affect diverse brain cell types remains poorly understood. Here, we combined subcellular-resolution spatial omics technologies, STARmap4 and RIBOmap5, to jointly resolve single-cell transcriptomes and translatomes for 3,447 genes in the brains of Grin2a+/- mice and their wild-type littermates across 538,188 cells. Translational dysregulation was markedly more prominent than transcriptional changes in neurons. Across neuronal subtypes, a set of genes including Camk2a, Arc, Egr1, Egr3, Chmp2b, and Pja2 exhibited translational reduction in a Grin2a gene dose-dependent fashion, suggesting a connection between NMDAR hypofunction and reduced protein synthesis of downstream synaptic plasticity effectors. In interneurons (particularly parvalbumin interneurons), a strong reduction of Gad2 translation implies loss of inhibitory function in cortical microcircuits, which has long been hypothesized for SCZ pathophysiology. Non-neuronal cell types including astrocytes, oligodendrocytes, and vascular cells also exhibited region-specific translational changes in neurotransmitter transport, lipid synthesis, myelination, and stress response pathways, some of which co-varied with regional neuron state. Together, our study reveals brain-wide translation dysregulation as a critical mechanism underlying SCZ pathophysiology.

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↗

bioRxiv2023

C4 induces pathological synaptic loss by impairing AMPAR trafficking.

During development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression of C4 (C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.

neuroscience↗