title: The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations.
abstract: Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO). β-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the forebrain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches.
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Michetti
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Castroflorio
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Marchionni
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Forte
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sterlini
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Binda
authors.affiliation: Department Head and Neck Neuroscience, Laboratory of Neurogenetics and Neuroscience, Institute G. Gaslini, Via Gerolamo Gaslini, 5, 16148 Genova, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Fruscione
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.affiliation: San Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
authors.affiliation: Department Head and Neck Neuroscience, Laboratory of Neurogenetics and Neuroscience, Institute G. Gaslini, Via Gerolamo Gaslini, 5, 16148 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Corradi
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy. Electronic address: fabio.benfenati@iit.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D000068079:Motor Disorders / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010433:Pentylenetetrazole; D010641:Phenotype; D012640:Seizures / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000473:pathology / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human; C000609581:PRRT2 protein, mouse; D010433:Pentylenetetrazole
keywords: Audiogenic seizures; Cerebellum; Hippocampus; Knockout mouse; Motor paroxysms; Proline-rich transmembrane protein 2; Synaptic transmission