The molecular mechanisms governing memory and forgetting in Caenorhabditis elegans

Mastrandreas, Pavlina. The molecular mechanisms governing memory and forgetting in Caenorhabditis elegans. 2020, Doctoral Thesis, University of Basel, Faculty of Psychology.


Official URL: https://edoc.unibas.ch/78907/

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One of the major goals of scientific research has been the study of the underlying neuropsychological and neurobiological components of learning and memory and how this knowledge can be exploited in order to diagnose as well as restore their dysfunction. In the current study we use C. elegans as a model to study the molecular mechanisms of associative memory with emphasis on two particular genes; the neural cell adhesion molecule 1 (NCAM-1) and the musashi RNA-binding protein family.
The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Using an interdisciplinary approach, we found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued the memory impairment, suggesting a conserved role of NCAM1in learning and memory. In parallel, DNA methylation of the NCAM1 promoter in two independent healthy Swiss cohorts was associated with memory performance. In two independent Sub-Saharan populations of conflict zone survivors who had faced severe trauma, DNA methylation at an alternative promoter of the NCAM1 gene was associated with traumatic memories. These results support a conserved role of NCAM1 in associative memory in nematodes and humans, and might, ultimately, be helpful in elucidating diagnostic markers or suggest novel therapy targets for memory-related disorders, like PTSD.
Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, it was shown that MSI1 actively promotes forgetting upon associative learning via a 3’ UTR-dependent translational repression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and their druggability in the modulation of forgetting. Expression of human MSI1 and MSI2 fully reversed decreased forgetting of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)- gossypol resulted in decreased forgetting, without causing locomotor, chemotactic or learning deficits. The effect of (-)- gossypol on memory is likely mediated via musashi as no drug effect was observed in msi-1(lf) treated worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of musashi might represent a promising novel drug approach for the treatment of memory deficits.
Moreover, it was shown that MSI-1 phosphorylation likely modulates protein activity during forgetting. Mass spectrometry revealed that MSI-1 is reproducibly phosphorylated at the T18, S19 and S34 residue sites. Separate and simultaneous T/S to A mutations of these sites resulted in inhibition of forgetting similar to deletion of msi-1. Emulating constitutive phosphorylation with msi-1(T18D) and msi-1(S19D) mutations, resulted in increased short-term memory retention and wild-type long-term memory. These results strongly suggest that phosphorylation of MSI-1 is necessary for its function.
Altogether, our findings shed light onto the opposing mechanisms regulating memory acquisition and memory loss and suggest that the targeting of these molecular pathways can help in the treatment of memory-related disorders.
Advisors:Papassotiropoulos, Andreas and de Quervain, Dominique J.-F.
Faculties and Departments:07 Faculty of Psychology > Departement Psychologie > Ehemalige Einheiten Psychologie > Molecular Neuroscience (Papassotiropoulos)
UniBasel Contributors:Papassotiropoulos, Andreas and de Quervain, Dominique J.-F.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14305
Thesis status:Complete
Number of Pages:118
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss143053
edoc DOI:
Last Modified:01 Oct 2021 09:16
Deposited On:01 Oct 2021 09:16

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