Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities.

Yaqiong Ren,Nuo Si,Yi Zhang,Lei Shi,Wanhai Xu,Xue Zhang,Yuqi Shen,Shiqi Fan

doi:10.3389/fgene.2021.639935

Abstract

BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

Highlights

Primary familial brain calcification (PFBC, OMIM#213600) is a rare autosomal dominant or recessive neurodegenerative and neuropsychiatric disorder characterized by bilateral symmetric cerebrovascular calcifications affecting multiple brain regions, the globus pallidus, caudate putamen, and thalamus in humans (Wang et al, 2012; Saleem et al, 2013)
The skeleton tended to be deformed in Slc20a2-HO mice, with a significant increase in physiological vertebral curvature (Figure 1D)
To investigate whether Slc20a2-PFBC mice could recapitulate the neurological abnormalities presented in patients with PFBC, we evaluated four classic behavioral paradigms (MWM, Y-maze, contextual and cued fear conditioning, and PPI)

Summary

Introduction

Primary familial brain calcification (PFBC, OMIM#213600) is a rare autosomal dominant or recessive neurodegenerative and neuropsychiatric disorder characterized by bilateral symmetric cerebrovascular calcifications affecting multiple brain regions, the globus pallidus, caudate putamen, and thalamus in humans (Wang et al, 2012; Saleem et al, 2013). Mutations in any of these genes that disrupt PDGFB–PDGFRB signaling are another genetic cause of idiopathic brain calcification, BBB and NVU impairments are inconclusive for PFBC pathophysiology (Keller et al, 2013; Nicolas et al, 2013b; Villasenor et al, 2017; Jensen et al, 2018). Primary familial brain calcification (PFBC, OMIM#213600), known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. Loss-offunction mutations in SLC20A2 are the major genetic causes of PFBC

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