Expanding the mouse repertoire of the synaptic activity-driven transcriptional program with a primate-specific gene: consequences for neuronal functions and cognitive abilities.
Final Report Abstract
Studies with rodents have shown that long-lasting adaptations crucial for cognitive functions like learning and memory, are based on the neuronal activity-driven transcriptional program, which involves several hundred genes. It was long believed that this activity-driven gene expression program is generic and shared across species, including humans. However, using iPSC-derived neurons, we and others identified a number of genes that distinguish the transcriptional response to activity in human neurons from that in rodent neurons. One of these genes, namely the primate-specific LINC00473 (Lnc473), was outstanding for its very strong activity-dependent transcriptional response. Intriguingly, this gene is downregulated in the brains of patients with schizophrenia and major depression, and its DNA copy number variations are associated with schizophrenia. In this study we investigated the functional impact of Lnc473 expression on neurons, focusing on its effects on gene regulation and electrophysiological properties. We cloned the full-length cDNA of human Lnc473 and produced a recombinant adeno-associated virus (rAAV) to express it in mouse neurons. We found that mouse neurons expressing human Lnc473 exhibited significant transcriptome alterations. Particularly, there was a substantial downregulation of epilepsy-associated genes, suggesting an impact on neuron and/or network excitability. Indeed, calcium imaging revealed that compared to control neurons, Lnc473-expressing mouse neurons showed an increased frequency of synchronous somatic calcium transients, typically evoked by trains of action potentials (APs). Additionally, while patch clamp recordings indicated that whole-cell capacitance, membrane resistance, and resting membrane potential were not altered, Lnc473 expression enhanced AP generation, increased AP amplitude, and brought the AP threshold potential closer to the resting membrane potential, demonstrating increased excitability of mouse neurons expressing this primate-specific gene. These effects were accompanied by an increased basal neuronal activity-mediated translocation of the CREB-regulated transcription coactivator Crtc1 into the nucleus, resulting in a surge in CREB-mediated transcription. Altogether, the results suggest that Lnc473 in primates may enhance the ability of CREB to increase intrinsic neuronal excitability, thereby potentially modulating plasticityrelated functions, such as memory.
Publications
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N-methyl-d-aspartate Receptor-mediated Preconditioning Mitigates Excitotoxicity in Human Induced Pluripotent Stem Cell-derived Brain Organoids. Neuroscience, 484, 83-97.
Bauersachs, Hanke Gwendolyn; Bengtson, C. Peter; Weiss, Ursula; Hellwig, Andrea; García-Vilela, Celia; Zaremba, Bastienne; Kaessmann, Henrik; Pruunsild, Priit & Bading, Hilmar
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Expression of the primate-specific LINC00473 RNA in mouse neurons promotes excitability and CREB-regulated transcription. Journal of Biological Chemistry, 299(5), 104671.
Pruunsild, Priit; Bengtson, C. Peter; Loss, Isabel; Lohrer, Benjamin & Bading, Hilmar
