Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning

Abstract

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep

“…Initial examination of SNPs in the AQP4-gene revealed a conserved haplotype spanning the entire gene with two common variants ( Figure 1B). This haplotype consists of eight SNPs, including rs335929 implicated in cognitive decline in Alzheimer's patients (16) and rs162008 demonstrated to reduce AQP4 expression (23).…”

“…To approximate a normal distribution, EEG power was log-transformed prior to statistical tests. Two-and three-way mixedmodel analysis of variance were performed with the between-subjects factor "genotype" (HtMa homozygotes vs. HtMi carriers) and the relevant within-subject factors: "condition" (baseline vs. recovery), "NREM sleep episode" (1-4), "frequency bin" (bin 1-81), clock time (8,11,14,17,20,23…”

“…These findings suggest a link between AQP4 and the development of brain diseases associated with waste deposition and fluid movements. Recently, a single variant within AQP4 was associated with a 15-20% change in AQP4 expression (23). (23), we hypothesized that the high AQP4 expressing variant (HtMa; black) presents with improved glymphatic flow compared to the low AQP4 expressing HtMi variant (red).…”

Plant and human aquaporins: pathogenesis from gut to brain

“…Although AQP4 is concentrated in the astrocytic foot process, it is also expressed, at lower concentrations, in other organs including the lung, thyroid, and stomach [20][21][22]. In the brain, AQP4 plays a role in neuroplasticity [23], the removal of waste from the brain [24], and the control of water into and out of the brain [25]. Indeed, the expression of AQP4 is greatly increased during cognitive stimulation, showing that it plays a positive role in neuroplasticity [23].…”

“…In the brain, AQP4 plays a role in neuroplasticity [23], the removal of waste from the brain [24], and the control of water into and out of the brain [25]. Indeed, the expression of AQP4 is greatly increased during cognitive stimulation, showing that it plays a positive role in neuroplasticity [23]. AQP4 serves as a trash chute for the removal of waste out of the brain and into circulation, where it can be processed and eliminated from the body [23].…”