A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

Hum Mol Genet. 2016 Jul 27;

Authors: Baroncelli L, Molinaro A, Cacciante F, Alessandrì MG, Napoli D, Putignano E, Tola J, Leuzzi V, Cioni G, Pizzorusso T

Abstract
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioral disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioral and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and accumulation of autofluorescent lipofucsin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.

PMID: 27466184 [PubMed - as supplied by publisher]

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