Biology subjects

Parra-Damas, A.

Publications and source records attributed to Parra-Damas, A..

3 recordsLinked to original sources

bioRxiv2025

Transcriptional and synaptic regulation of NMDA glutamate receptor-mediated hippocampal plasticity and memory

Synapse-to-nucleus signaling regulates activity-dependent synaptic plasticity underlying memory by linking N-methyl-D-aspartate (NMDA) glutamate receptors (GluN) to gene transcription mediated by the transcription factor cAMP-response element binding protein (CREB), but the underlying gene programs mediating potentiation at excitatory synapses are unknown. Here, we analyzed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) datasets of mouse and human CREB and the synaptonuclear factor CREB-regulated transcription coactivator1 (CRTC1) to identify relevant target genes and biological pathways coupling neuronal activity to synaptic function/plasticity. Our analyses indicate that CRTC1 specifically couples neuronal activity with synaptic plasticity by binding to conserved promoters of CREB target genes comprising inducible transcription factors (including c fos, Crem, Npas4 and Nr4a1-3), and neuronal excitability and plasticity genes, including Ntrk2, Homer1, Dlg4 (PSD-95) and the NMDA receptor subunit Grin1 (GluN1). CRTC1/CREB target genes were highly enriched in gene ontology (GO) nuclear terms, including several members of the CREB family, and transcriptional modulators and repressors. Interestingly, GO enrichment and protein-protein interaction (PPI) network analyses revealed that genes mediating synapse-to-nucleus signaling (including most known synaptonuclear factors and direct interacting modulators) are collectively regulated by CREB/CRTC1, and that protein kinase C (PKC) is a key interactor of the CRTC1/14-3-3 complex at synapses. In agreement with these in silico analyses, we show that CRTC1 regulates synaptic activity-dependent phosphorylation and synaptic recruitment of GluN1 mediated by PKC in hippocampal neurons, and that PKC activation reverses NMDA receptor-mediated currents and long-term potentiation (LTP) deficits caused by CRTC1 silencing in the hippocampus. Consistent with genomics and functional data, morphological and behavioral analyses show crucial roles of CRTC1 on dendritic spine structure, plasticity, and hippocampal-dependent associative memory. Our results support a model in which neuronal activity and synaptic inputs are integrated in the nucleus through conserved CREB/CRTC1-regulated transcriptional programs sustaining global synapse-to-nucleus signaling pathways impacting on synaptic plasticity and memory.

neuroscience↗

bioRxiv2023

Differential neural circuit vulnerability to β-amyloid and tau pathologies in novel Alzheimer disease mice

Alzheimers disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-{beta} (A{beta}) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubule-associated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to A{beta} pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to A{beta}/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g., APOE, BIN1, CD33, CLU, PICALM, PLCG2, PTK2B, TREM2, SORL1, USP6NL) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of A{beta} and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of A{beta} and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies. Graphical abstractAge-dependent vulnerability of memory and emotional neural circuits in response to tau and A{beta} pathologies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/536603v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@efbe90org.highwire.dtl.DTLVardef@1c7f1dborg.highwire.dtl.DTLVardef@1d7764borg.highwire.dtl.DTLVardef@9738ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Deep learning reveals cancer metastasis and therapeutic antibody targeting in whole body

Reliable detection of disseminated tumor cells and of the biodistribution of tumor-targeting therapeutic antibodies within the entire body has long been needed to better understand and treat cancer metastasis. Here, we developed an integrated pipeline for automated quantification of cancer metastases and therapeutic antibody targeting, named DeepMACT. First, we enhanced the fluorescent signal of tumor cells more than 100-fold by applying the vDISCO method to image single cancer cells in intact transparent mice. Second, we developed deep learning algorithms for automated quantification of metastases with an accuracy matching human expert manual annotation. Deep learning-based quantifications in a model of spontaneous metastasis using human breast cancer cells allowed us to systematically analyze clinically relevant features such as size, shape, spatial distribution, and the degree to which metastases are targeted by a therapeutic monoclonal antibody in whole mice. DeepMACT can thus considerably improve the discovery of effective therapeutic strategies for metastatic cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/541862v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@ffe1b9org.highwire.dtl.DTLVardef@13c55eborg.highwire.dtl.DTLVardef@2ccb6corg.highwire.dtl.DTLVardef@df55e9_HPS_FORMAT_FIGEXP M_FIG C_FIG Supplementary Movies and deep learning algorithms of DeepMACT are available at http://discotechnologies.org/DeepMACT/

cancer biology↗