title: Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation.
abstract: Hypomorphic mutations in the gene encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme, ALPL in human or Akp2 in mice, cause hypophosphatasia (HPP), an inherited metabolic bone disease also characterized by spontaneous seizures. Initially, these seizures were attributed to the impairment of GABAergic neurotransmission caused by altered vitamin B6 (vit-B6) metabolism. However, clinical cases in human newborns and adults whose convulsions are refractory to pro-GABAergic drugs but controlled by the vit-B6 administration, suggest that other factors are involved. Here, to evaluate whether neurodevelopmental alterations are underlying the seizures associated to HPP, we performed morphological and functional characterization of postnatal homozygous TNAP null mice, a model of HPP. These analyses revealed that TNAP deficient mice present an increased proliferation of neural precursors, an altered neuronal morphology, and an augmented neuronal activity. We found that these alterations were associated with a partial downregulation of the purinergic P2X7 receptor (P2X7R). Even though deficient P2X7R mice present similar neurodevelopmental alterations, they do not develop neonatal seizures. Accordingly, we found that the additional blockage of P2X7R prevent convulsions and extend the lifespan of mice lacking TNAP. In agreement with these findings, we also found that exogenous administration of ATP or TNAP antagonists induced seizures in adult wild-type mice by activating P2X7R. Finally, our results also indicate that the anticonvulsive effects attributed to vit-B6 may be due to its capacity to block P2X7R. Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP.
authors.affiliation: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Sebastián-Serrano
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: de Diego-García
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain and.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Olivos-Oré
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain and.
authors.forename: Marina
authors.initials: M
authors.lastname: Arribas-Blázquez
authors.affiliation: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Frailes
authors.affiliation: Department of Medicine and Animal Surgery, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-Díaz
authors.affiliation: Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain and.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Artalejo
authors.affiliation: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda. Puerta de Hierro S/N, Madrid, Spain migueldiaz@ucm.es.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Díaz-Hernández
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007014:Hypophosphatasia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis / Q000235:genetics*; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D025101:Vitamin B 6 / Q000008:administration & dosage
chemical_list: D058486:Receptors, Purinergic P2X7; D025101:Vitamin B 6; D000255:Adenosine Triphosphate; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase; D002118:Calcium