Journal
EXPERIMENTAL NEUROLOGY
Volume 328, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2020.113283
Keywords
Alzheimer's disease; Prion disease; Epileptic seizures; Convulsants; Synapse physiology; Zebrafish; CRISPR; Neural development; Animal model
Categories
Funding
- Alberta Prion Research Institute-Alberta Innovates BioSolutions
- Alzheimer Society of Alberta and the Northwest Territories
- Alzheimer Society of Canada
- Alberta Innovates Health Solutions
- SynAD postdoctoral fellowship via Alzheimer Society of Alberta and Northwest Territories
- University Hospital Foundation
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It has been proposed that Amyloid beta Precursor Protein (APP) might act as a rheostat controlling neuronal excitability, but mechanisms have remained untested. APP and its catabolite A beta are known to impact upon synapse function and dysfunction via their interaction with the prion protein (PrPC), suggesting a candidate pathway. Here we test if PrPC is required for this APP function in vivo, perhaps via modulating mGluR5 ion channels. We engineered zebrafish to lack homologs of PrPC and APP, allowing us to assess their purported genetic and physiological interactions in CNS development. We generated four appa null alleles as well as prp1(-/-);appa(-/-) double mutants (engineering of prp1 mutant alleles is described elsewhere). Unexpectedly, appa(-/-)and compound prp1(-/-);appa(-/-) mutants are viable and lacked overt phenotypes (except being slightly smaller than wildtype fish at some developmental stages). Zebrafish prp1(-/-) mutants were substantially more sensitive to appa knockdown than wildtype fish, and both zebrafish prp1 and mammalian Prnp mRNA were significantly able to partially rescue this effect. Further, appa(-/-) mutants exhibited increased seizures upon exposure to low doses of convulsant. The mechanism of this seizure susceptibility requires prp1 insomuch that seizures were significantly dampened to wildtype levels in prp1(-/-);appa(-/-) mutants. Inhibiting mGluR5 channels, which may be downstream of PrPC, increased seizure intensity only in prp1(-/-) mutants, and this seizure mechanism required intact appa. Taken together, these results support an intriguing genetic interaction between prp1 and appa with their shared roles impacting upon neuron hyperexcitability, thus complementing and extending past works detailing their biochemical interaction(s).
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