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Carboxypeptidase A6 (CPA6) is an extracellular matrix metallocarboxypeptidase that modulates peptide and protein function by removal of hydrophobic C-terminal amino acids. Mutations in the human  CPA6  gene that reduce enzymatic activity in the extracellular matrix are associated with febrile seizures, temporal lobe epilepsy, and juvenile myoclonic epilepsy. The characterization of these human mutations suggests a dominant mode of inheritance by haploinsufficiency through loss of function mutations, however the total number of humans with pathologic mutations in  CPA6  identified to date remains small. To better understand the relationship between CPA6 and seizures we investigated the effects of morpholino knockdown of  cpa6  mRNA in zebrafish ( Danio rerio ) larvae. Knockdown of  cpa6  mRNA resulted in resistance to the effect of seizure-inducing drugs pentylenetetrazole and pilocarpine on swimming behaviors. Knockdown of  cpa6  mRNA also reduced the levels of mRNAs encoding neuropeptide precursors ( bdnf ,  npy ,  chga ,  pcsk1nl ,  tac1 ,  nts ,  edn1 ), a neuropeptide processing enzyme ( cpe ), transcription factor ( c-fos ), and molecules implicated in glutamatergic signaling ( grin1a  and  slc1a2b ). Treatment of zebrafish embryos with 60 mM pilocarpine for 1 hour led to reductions in levels of many of the same mRNAs when measured 1 day after pilocarpine exposure, except for  c-fos  which was elevated 1 day after pilocarpine treatment. Pilocarpine treatment, like  cpa6  knockdown, led to a reduced sensitivity to pentylenetetrazole when tested 1 day after pilocarpine treatment. Taken together, these results add to mounting evidence that peptidergic systems participate in the biological effects of seizure-inducing drugs, and are the first  in vivo  demonstration of the molecular and behavioral consequences of  cpa6  insufficiency.

plos one

Knockdown of Carboxypeptidase A6 in Zebrafish Larvae Reduces Response to Seizure-Inducing Drugs and Causes Changes in the Level of mRNAs Encoding Signaling Molecules