Biology subjects

Juengling, M.

Publications and source records attributed to Juengling, M..

3 recordsLinked to original sources

bioRxiv2026

Local consequences of FMRP loss: cell type-specific mRNA and protein profiles of Fmr1-KO synapses

Brain function relies on billions of neurons interconnected by synapses with unique molecular composition specialized for cell type, brain region, and their role in circuit dynamics. Pathological synaptic dysfunctions - so-called synaptopathies - underlie many neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). While synaptic deficits are well documented in FXS, molecular studies have largely relied on bulk brain homogenates or synaptic fractions, which typically represent ''average'' molecular identities, potentially masking synapse type-specific alterations. To provide synapse type resolution, we use fluorescence-activated synaptosome sorting coupled to RNA-sequencing and mass spectrometry to isolate and profile cortical excitatory and inhibitory synapses of hemizygous and heterozygous Fmr1-deficient mice. We found that full or partial FMRP loss leads to cell type- and compartment-specific molecular remodeling (syndive.org), affecting mRNAs and proteins related to synaptic organization and metabolic pathways. Strikingly, only a minority of dysregulated mRNAs/proteins were shared across excitatory and inhibitory synapses - the substantial majority were uniquely regulated at one subtype. Indeed, FMRP loss often resulted in opposing protein changes in each synapse type. Changes in mRNA or protein abundance were also not well coordinated, consistent with substantial post-transcriptional regulation, including changes to the translational and ubiquitin-dependent protein degradation machinery. For example, our data suggest a disturbed, cell type-distinct coordination of protein degradation via CAND1 as one key consequence of FMRP loss. Furthermore, we observed differences in male (Fmr1-/y) and female (Fmr1-/+) transcriptomes, where, for example, FMRP dosage was coupled to reciprocal regulation of the NDD-risk gene Trpc4 in both synapse types.

neuroscience↗

bioRxiv2025

Brain-wide synaptosome profiling reveals localized mRNAs that diversify synapses

Chemical synapses are the principal communication nodes of the brain, defined by their specialization and plasticity. Their diversity spans multiple levels, from the polarity and magnitude of electrophysiological responses to the proteins driving these differences. Here, we describe another layer of synapse diversity - synaptic transcriptome diversity. Using transgenic mice to fluorescently label presynapses in Camk2a-, Gad2-, DAT-, PV-, SST-, and VIP-expressing neurons, combined with fluorescence-activated synaptosome sorting, we profiled synaptic transcriptomes across five brain regions. We identified [~]4000 mRNAs enriched at synapses - some type-specific, others shared - and highlight region-specific enrichments of mRNAs encoding protein subunits or family members. We found that the abundance of synaptic mRNAs is not a passive reflection of their abundance in cellular somata, indicating active trafficking and sorting mechanisms. Integrating transcriptomic and proteomic data, we identified [~]90 genes with significantly correlated mRNA-protein ratios across regions, mainly involved in synaptic vesicle dynamics, receptor signaling, and calcium regulation, suggesting a key role for local translation in maintaining protein copy number. Although synaptic mRNAs represent only a fraction of the templates for the synaptic proteome, the synaptic transcriptome reflects the synapse diversity captured by the proteome equally well. Together, this dataset (https://syndive.org/) provides a resource for exploring how synaptic mRNA localization and local translation shape synaptic identity and function.

neuroscience↗

bioRxiv2024

The molecular diversity of hippocampal regions and strata at synaptic resolution revealed by integrated transcriptomic and proteomic profiling

The molecular diversity of neurons and their synapses underlies the different responses and plasticity profiles that drive all neural circuits and behavior. While the extent of this diversity has been partially revealed by transcriptomic and proteomic profiling, combined studies of neuronal transcripts and proteins are limited. Here, we used microdissection of mouse hippocampal subregions and CA1 strata and fluorescence-activated synaptosome sorting (FASS) to characterize the transcripts and proteins from different hippocampal neurons and their compartments with synaptic resolution. Parallel RNA-seq and LC-MS/MS of microdissections identified over 15,000 mRNA transcripts and 10,000 proteins, revealing thousands with local enrichment such as classes of glutamate receptors and voltage-gated potassium channels, myelin-associated molecules, and adhesion molecules. Synaptosome analysis further identified specific enrichment of molecules from collagen, ribosome, solute carrier, and receptor families at different synapses formed along CA1 neurons. By integrating mRNA and protein data, we defined clusters of co-regulated molecules such as adhesion and neurofilament proteins and transporter mRNAs, and found subsets of mRNA-protein pairs with strong correlation and anti-correlation in their abundance variation. Our findings comprise a rich resource on the molecular landscape of the hippocampus and its synapses that is accessible at syndive.org, and highlight the coordinated organization of transcripts and proteins between regions, neuronal compartments, and synapses.

neuroscience↗