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

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 behavioural 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 behavioural 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 the accumulation of autofluorescent lipofuscin. 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.

Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain

“…Indeed, expression of Slc6a8 and Hcn2 were strongly correlated and high in fast-firing cell types (Figure 4E). Our data suggest human neurological symptoms associated with Slc6a8 mutations (van de Kamp et al, 2013) may in part be due to deficits in fast-firing neurons, consistent with cortical GABAergic synapse loss observed in mouse models (Baroncelli et al, 2017). Gene co-expression relationships across large numbers of cell types yield new hypotheses about genes, brain circuitry, and disease.…”

Cognitive deficits and increases in creatine precursors in a brain‐specific knockout of the creatine transporter gene Slc6a8

“…These mice show deficits in NOR and Y-maze performance. 13 While this supports the hypothesis that the effects are centrally mediated, the lack of MWM testing in these mice still leaves the possibility that the larger spatial learning deficit seen in Slc6a8 ( 2–4 ) − /y mice are due to motor deficits–a confound that must be resolved in order to properly model this disorder.…”

“…12 Interestingly, this deficit did not fully replicate in a subsequent study when similarly aged mice showed a deficit only on day 5 of testing. 13 This would suggest that both our ubiquitous and our bKO mice have more severe spatial learning deficits than the ubiquitous 5 to 7 deletion. The brain-specific knockout of exons 5 to 7 mice were not evaluated in the MWM.…”

“…Baroncelli et al 13 showed that a Nestin-cre -generated brain-specific knockout of exons 5 to 7 of the Slc6a8 gene resulted in NOR and spontaneous alternation deficits. Ubiquitous deletion of the same region results in MWM deficits, but only when the last 3 days of testing were examined separately.…”

A Single-Cell Atlas of Cell Types, States, and Other Transcriptional Patterns from Nine Regions of the Adult Mouse Brain

“…Our data suggest that Slc6a8 plays an enhanced role in fastspiking cells -which would include Pvalb + basket cells, the resident fast-firing inhibitory neurons in cortical areas known to seed seizures. Indeed, male mice with mutations in (x-linked) Slc6a8 have fewer GABAergic synapses (Baroncelli et al, 2017). These data highlight how analyses of gene co-expression across a large number of cell types can nominate new hypotheses about genes, brain circuitry, and disease.…”