Expanding the mouse repertoire of the synaptic activity-driven transcriptional program with a primate-specific gene: consequences for neuronal functions and cognitive abilities.

• Applicant: Professor Dr. Hilmar Bading
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441538814

Neuronal activity-driven gene expression is the basis for long-lasting adaptations of the brain that are crucial for cognitive functions including learning and memory. The functions of prominent activity-induced genes, such as Bdnf, Egr1 or Npas4, have been mostly examined in rodents. These studies have revealed central, plasticity-related functions for them and it is generally believed that, in principle, their roles are conserved in other mammalian species, including primates and humans. By and large, this is most likely correct. However, the activity-driven gene expression program is not fully generic and not identical between species. For example, it has been shown recently that a small number of the genes that are turned on by synaptic activity in human neurons do not have orthologs in rodents. One of those genes that stands out is the long non-coding RNA gene, LINC00473, a primate-specific gene that is rapidly and particularly robustly upregulated by synaptic activity in human neurons. However, as anticipated for a gene that lacks a mouse counterpart, its functions in neurons are uncharacterized. Since the activity-driven gene expression program is required for cognitive functions, we hypothesize that LINC00473 may have influenced the evolution of brain functions in the lineage leading to humans. Our preliminary data show that humanizing mouse neurons with LINC00473 expression affects plasticity-associated processes, a result that is in line with our hypothesis. In this project, we propose to use gain-of-function experiments in mouse neurons in culture and in mice in vivo, as well as loss-of-function approaches with human iPS cell-derived neurons to study the impact of the primate-specific gene, LINC00473 on neuronal morphology, intracellular signaling, gene regulation and electrophysiological properties, as well as the underlying mechanisms. Behavior studies will be done to examine if humanizing mouse neurons via expansion of the mouse transcriptome with an eminent primate-specific, activity responsive gene affects cognitive performance. Identification of the functions of LINC00473 in neurons may reveal mechanisms that have taken part in driving evolutionary enhancement of human cognitive abilities.

• DFG Programme: Research Grants