Neurodegenerative Disease: a Social Role for Microrna

RESEARCH HIGHLIGHTS

Nature Reviews Neuroscience | AOP, published online 3 December 2014; doi:10.1038/nrn3884

NEURODEGENERATIVE DISEASE A social role for microRNA Frontotemporal dementia (FTD) is Investigating the molecular basis The findings suggested that characterized by changes in social of this impairment in sociability, the decreased suppression of AMPAR an behaviour, among other symptoms. authors found that gene and protein subunits — and GRIA2 in particu- intraperitoneal The molecular and cellular mecha- expression of the AMPAR subunits lar — by miR-124, which results in nisms underlying these changes GRIA2, GRIA3 and GRIA4 were altered AMPAR function, can con- injection of are not known, but a new study increased in the cortex of 4- and tribute to impairments in sociability. an AMPAR shows that they may involve altered 8-month-old CHMP2BIntron5 transgenic Supporting this notion, cortical antagonist AMPA receptor (AMPAR) subunit mice compared with wild-type con- expression of miR-124 was reduced increased composition caused by reduced trols. In addition, electrophysiology and expression of GRIA2 and GRIA4 microRNA 124 (miR-124) levels in data were suggestive of an increased was increased in post-mortem cortex sociability in the frontal cortex. proportion of GRIA2-containing, samples from patients with FTD 8-month-old Mutations in the gene encoding Ca2+-impermeable AMPARs over who had deficits in social behaviour. CHMP2BIntron5 charged multivesicular body pro- non-GRIA2-containing AMPARs Moreover, in 8-week-old neurons tein 2B (CHMP2B) have been impli- in the frontal cortex of 4-month-old (but not in 2-week-old neurons) transgenic mice cated in FTD. Gascon et al. generated transgenic mice. obtained from induced pluripotent transgenic mice in which a mutated These findings indicated a stem cell lines derived from such form of the human CHMP2B gene possible link between changes in patients, miR-124 expression was was expressed in forebrain neurons. cortical AMPAR function and lower and GRIA2 and GRIA4 mRNA Although these CHMP2BIntron5 trans- impairments in sociability. Indeed, expression was higher than expres- genic mice showed similar social an intraperitoneal injection of an sion levels in neurons from control recognition and social memory to AMPAR antagonist increased socia- lines. In addition, viral expression wild-type controls, they spent less bility in 8-month-old CHMP2BIntron5 of miR-124 in the frontal cortex of time interacting with other mice at transgenic mice but had no effect in 7-month-old CHMP2BIntron5 trans- 4 and 8 months of age, but not at wild-type controls. genic mice reduced Gria2 and Gria4 earlier ages. The authors next examined mRNA levels in this brain area and whether miRNAs play a part in the increased sociability from 1 month ImageSource upregulation of the AMPAR subunits. post-injection onwards. Similarly, They found that levels of miR-124 — silencing cortical Gria2 expression one of the most abundant microRNAs using RNA interference partially in the brain — were reduced in the reversed the impairment in sociability cortex of CHMP2BIntron5 transgenic in CHMP2BIntron5 transgenic mice. mice relative to wild-type controls Together, these findings suggest and that preventing the expression that altered social behaviour in FTD of the mutant gene normalized may be due, at least in part, to a miR-124 levels. Computer models reduction in miR-124 levels — which and in vitro data indicated that could itself be caused by mutations Gria2, Gria3 and Gria4 mRNAs are in CHMP2B — resulting in altered potential targets for suppression by AMPAR composition and function miR-124. Furthermore, miR-124 in the frontal cortex. expression decreased with age in the Leonie Welberg cortex of CHMP2BIntron5 transgenic ORIGINAL RESEARCH PAPER Gascon, E. et al. mice, coinciding with the increase in Alterations in microRNA-124 and AMPA receptors cortical GRIA2, GRIA3 and GRIA4 contribute to social behavioral deficits in levels and the appearance of impaired frontotemporal dementia. Nature Med. http://dx. doi.org/10.1038/nm.3717 (2014) sociability.

NATURE REVIEWS | NEUROSCIENCE VOLUME 16 | JANUARY 2015