Hypophosphatasia (
HPP) is a rare heritable
metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific
alkaline phosphatase (TNAP)
enzyme. In addition to skeletal and dental malformations, severe forms of
HPP are also characterized by the presence of spontaneous
seizures. Initially, these
seizures were attributed to an impairment of GABAergic neurotransmission caused by altered
vitamin B6 metabolism. However, recent work by our group using knockout mice null for TNAP (TNAP-/-), a well-described model of infantile
HPP, has revealed a deregulation of purinergic signaling contributing to the seizure phenotype. In the present study, we report that adult heterozygous (TNAP+/-) transgenic mice with decreased TNAP activity in the brain are more susceptible to
adenosine 5'-triphosphate (
ATP)-induced
seizures. Interestingly, when we analyzed the extracellular levels of
ATP in the cerebrospinal fluid, we found that TNAP+/- mice present lower levels than control mice. To elucidate the underlying mechanism, we evaluated the expression levels of other ectonucleotidases, as well as different
proteins involved in
ATP release, such as pannexin,
connexins, and vesicular
nucleotide transporter. Among these, Pannexin-1 (Panx1) was the only one showing diminished levels in the brains of TNAP+/- mice. Altogether, these findings suggest that a physiological regulation of extracellular
ATP levels and Panx1 changes may compensate for the reduced TNAP activity in this model of
HPP.