“…Gene expression was mostly downregulated, and, as expected, the largest changes in gene expression occurred in clusters where Silc1 expression was highest: 1, 3–5, and 7–8, all of which had low Prox1 expression, suggesting that they corresponded to cells outside of the DG, and of which clusters 3 and 4 had the highest Mgat4 expression, suggesting that these are CA3 cells ( Figures 7 B and 7C). Notably, four of these clusters were enriched with genes positively regulated by Sox11 in other studies 28 , 51 , 52 (“known” targets in Figure 7 C), suggesting that at least some of the changes in gene expression occur through changes in Sox11 activity. Figure 7 Differences in cell-type-specific gene expression and chromatin accessibility in the Silc1 −/− hippocampus (A) UMAP visualization of the snRNA-seq expression data, with color coding of the 22 clusters of cells.…”
Section: Resultsmentioning
confidence: 65%
“…These genes were also significantly upregulated in published datasets of AAV-mediated SOX11 induction in the DG 28 and retinal ganglion cells (RGCs). 51 While some of the genes were also downregulated in the dentate neuroepithelium at embryonic day 13.5 (E13.5) in embryos lacking SOX11, specifically in the telencephalon, 52 the difference was not significant when considering these genes as a group. Further supporting the 33 genes being tightly associated with Sox11 activity, Enrichr 5 found that they were enriched with genes co-expressed with human SOX11 in the ARCHS4 database (adjusted p = 2 × 10 −5 ; odds ratio, 16.84).…”
“…Gene expression was mostly downregulated, and, as expected, the largest changes in gene expression occurred in clusters where Silc1 expression was highest: 1, 3–5, and 7–8, all of which had low Prox1 expression, suggesting that they corresponded to cells outside of the DG, and of which clusters 3 and 4 had the highest Mgat4 expression, suggesting that these are CA3 cells ( Figures 7 B and 7C). Notably, four of these clusters were enriched with genes positively regulated by Sox11 in other studies 28 , 51 , 52 (“known” targets in Figure 7 C), suggesting that at least some of the changes in gene expression occur through changes in Sox11 activity. Figure 7 Differences in cell-type-specific gene expression and chromatin accessibility in the Silc1 −/− hippocampus (A) UMAP visualization of the snRNA-seq expression data, with color coding of the 22 clusters of cells.…”
Section: Resultsmentioning
confidence: 65%
“…These genes were also significantly upregulated in published datasets of AAV-mediated SOX11 induction in the DG 28 and retinal ganglion cells (RGCs). 51 While some of the genes were also downregulated in the dentate neuroepithelium at embryonic day 13.5 (E13.5) in embryos lacking SOX11, specifically in the telencephalon, 52 the difference was not significant when considering these genes as a group. Further supporting the 33 genes being tightly associated with Sox11 activity, Enrichr 5 found that they were enriched with genes co-expressed with human SOX11 in the ARCHS4 database (adjusted p = 2 × 10 −5 ; odds ratio, 16.84).…”
“…These genes were also significantly up-regulated in published datasets of AAV-mediated SOX11 induction in the DG (von Wittgenstein et al 2020) and retinal ganglion cells (RGCs) (Chang et al 2021). While some of the genes were also down-regulated in the dentate neuroepithelium at E13.5 in the embryos lacking SOX11, specifically in the telencephalon (Abulaiti et al 2022), the difference was not significant considering these genes as a group. Further supporting the 33 genes being tightly associated with Sox11 activity, Enrichr (Chen et al 2013) found that they were enriched with genes co-expressed with human SOX11 in the ARCH4 database (adjusted P=2×10 -5 , odds-ratio 16.84).…”
Section: Resultsmentioning
confidence: 86%
“…RNA-seq reads were mapped to the mouse genome (mm10 assembly) using STAR (Dobin et al 2013) to generate read coverage tracks visualized using the UCSC genome browser. RSEM (Li and Dewey 2011) with RefSeq annotations was used to call differential expression between samples with data collected in this study and data from public datasets on OEof Sox11 in the hippocampus: SOX11 induction in the DG (von Wittgenstein et al 2020) – SRP229390; SOX11 induction and in RGCs (Chang et al 2021) – SRP290800; dentate neuroepithelium at E13.5 in the embryos lacking SOX11 (Abulaiti et al 2022) – SRP285830; aging hippocampus and cortex – SRP309056. Differential expression between conditions was called using DESeq2 with default parameters (Love, Anders, and Huber 2014).…”
Long noncoding RNAs (lncRNAs) are expressed in many brain circuits and neuronal types, but their significance to normal brain functions has remained largely unknown. Here, we study the functions in the central nervous system of Silc1, a lncRNA we previously showed to be important for neuroregeneration in the peripheral nervous system. We found that Silc1 is rapidly and strongly induced upon stimulation in the hippocampus and is required for efficient spatial learning. Silc1 production is important for the induction of Sox11 (its cis-regulated target gene) throughout the CA1-CA3 regions and the proper expression of key Sox11 target genes. Consistent with its newly found role in neuronal plasticity, we find that during aging and in models of Alzheimer's disease Silc1 levels decline. Overall, we uncover a novel plasticity pathway, in which Silc1 acts as an immediate-early gene to activate Sox11 to induce a neuronal growth-associated transcriptional program important for memory formation.
“…As previously stated, the deletion of the NMDAR subunit GluN1 was reported to trigger hyperexcitability of CA3 pyramidal cells and deficits in social interaction, and elevated fear (Segev et al, 2020). Likewise, the downregulation of SOX11, a protein associated with an increased risk of schizophrenia, causes abnormal functionality of the MFs and mimics behavioral abnormalities associated with schizophrenia, such as impaired startle response, anxiety, and decreased social interaction (Abulaiti et al, 2022). Together, these behavioral observations indicate that interfering with the proper functioning of the DG—CA3 network could reproduce behavioral hallmarks of schizophrenia.…”
Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK‐801 during early postnatal development alters glutamate release and impairs the induction of NMDAR‐dependent long‐term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)‐mediated short‐ and long‐term potentiation, are compromised in response to neonatal treatment with MK‐801. Consistent with this tenet, short‐ and long‐term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole‐cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre‐ and postsynaptic modifications at the MF—CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired‐pulse ratio, and reduced AMPAR‐mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK‐801‐treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR‐independent forms of synaptic plasticity of the hippocampus.
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