Amyloid-β precursor protein mutant zebrafish exhibit seizure susceptibility that depends on prion protein.

It has been proposed that Amyloid β Precursor Protein (APP) might act as a rheostat controlling neuronal excitability, but mechanisms have remained untested. APP and its catabolite Aβ are known to impact upon synapse function and dysfunction via their interaction with the prion protein (PrP^C), suggesting a candidate pathway. Here we test if PrP^C is required for this APP function in vivo, perhaps via modulating mGluR5 ion channels. We engineered zebrafish to lack homologs of PrP^C 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 PrP^C, 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).