Introduction:

Visual and cognitive impairment usually co‐occur, particularly in the elderly [1]. Just very recently, in secondary analysis of a prospective longitudinal cohort study of older women with formal vision, it was found that objective visual impairment is associated with an increased risk of incident dementia [2]. Furthermore, results of the only interventional study in patients with dementia clearly provided the first experimental proof that vision and hearing improvement (by merely prescribing and fitting of lenses or hearing aids) has a positive impact on neuropsychiatric symptoms [3]. The surprise is that other interventions such as cataract surgery reduce the risk of developing mild cognitive impairment -albeit not for severe dementia- independently of visual acuity [4]. Even more interesting is the results of study carried out by Cavézian et al [5] that shows that children with an ophthalmologic disorder may experience difficulties with visuospatial tasks despite corrected-to-normal visual acuity.

These reports suggest that there might be a common mechanism by which cognitive impairments specifically link to specific ocular problems. Ruiter et al described unusual case of a 28-year-old woman with an aquaporin4 (AQP4) antibody-seropositive neuromyelitis optica spectrum disorder who presented with cognitive impairment, symptoms of psychosis and autonomic dysregulation [6]. Similar psychiatric symptoms have been previously described before in a few cases [7-13]. One might further question whether there is a causal relationship between particular cognitive features (such as memory deficits, etc.) and visual acuity and/or ocular situations; and whether there are common elements between these two?

For the purpose of this short communication, we focus on aquaporins (AQPs) and only visual and cognitive evidence. AQPs are integral are channel proteins and their main function is to facilitate transport of water across cell membranes in response to osmotic gradients [14]. AQPs are widely expressed and distributed in the nervous system and eye.

AQPs in the brain and eye:

AQPs in the brain:

Three types of aquaporins (AQP1, AQP4 and AQO9) are expressed in the brain. AQP4 as the most predominant brain water channel is expressed in astrocyte endfeet facing brain capillaries, nodes of Ranvier and perisynaptic spaces. It is involved in brain edema formation and resolution, and clearance of K+ released during neuronal activity. AQP1, which is expressed in epithelial cells of choroid plexus is mostly involved in cerebrospinal fluid formation. Finally, AQP9, which is present in astrocytes and in subpopulations of neurons, is involved in the brain energetic.

AQPs in the human lens:

At the ocular surface, it is known that AQP1 is expressed in corneal endothelium [15], AQP3 and AQP5 in corneal epithelium [16], and AQP3 in conjunctival epithelium [17]. AQP0 is expressed in lens fiber cells, AQP1 in lens epithelium, AQP1, AQP4 are expressed in ciliary epithelium and AQP4 is expressed in retinal Müller cells [16].

On the other hand, by playing central roles in the maintenance of ocular lens homeostasis, some AQPs (AQP0, AQP1 and AQP5) contribute to the establishment and maintenance of the overall optical properties of the human lens. Three aquaporins, AQP0, AQP1 and AQP5, each with differential functional properties, are extensively and differentially expressed in the different regions of the human lens.
Furthermore, the diversity of AQP functionality is increased in the absence of protein turnover by age-related modifications to lens AQPs that are proposed to alter AQP function in the different regions of the lens. These regional differences in AQP functionality are proposed to contribute to the generation and directionality of the lens internal microcirculation; a system of circulating ionic and fluid fluxes that delivers nutrients to and removes wastes from the lens faster than could be achieved by passive diffusion alone. In this review, we present how regional differences in lens AQP isoforms potentially contribute to this microcirculation system by highlighting current areas of investigation and emphasizing areas where future work is required. [18].

AQPs, myopia and memory:

AQP4 and AQP1, the two primary AQPs of the central nervous system CNS), regulate brain water and cerebrospinal fluid (CSF) movement and contribute to vasogenic and cytotoxic edema, where they control the size of the extracellular and intracellular fluid volumes, respectively. AQP4 is crucial to dysfunctions in glutamate metabolism, synaptogenesis, and memory consolidation [19].

AQPs and myopia:

Goodyear et al were the first to demonstrate the presence of AQP4 protein in the chick retina. They showed the association of AQP4 expression in the inner retina with the initiation of form deprivation and the period of fastest axial elongation. The increased expression of AQP4 channels near the vitread border during the time of rapid growth suggested a novel role for AQP4 as a channel for movement of retinal fluid into the vitreous in form-deprived chicks [20]. Here, it is crucial to recall that AQP4 is the predominant AQP in the mammalian retina, which is reported to be highly expressed on the Müller glial cells. By modifying the neurotransmitters, concentrations of ions, and other neuroactive substances within the extracellular space between the inner and the outer limiting membrane, Müller cells modulate neuronal activity. Müller cells preserve extracellular homeostasis, particularly with regard to the spatial buffering of extracellular potassium (K+) via inward rectifying K+ channels (i.e., Kir channels). Both AQP4 and Kir channels are involved in regulating the extracellular environment in the retina and brain. In a brilliant review, Goodyear et al extensively discussed that during light activation AQP4 channels are possibly to be the conduit for facilitating fluid homeostasis in the inner retina. AQP4 channels play a role in the regulation of ocular volume and growth. Within the review, they cite some researches showing that the level of AQP4 expression is tightly associated with environmentally driven manipulations of light activity on the retina, and consequently, the development of myopia [20].

Furthermore, two recent state-of-the-art studies have shown that AQP-1 depletion downregulates the sclera biomechanical strength through changing of choroidal thickness (CT) and axial length, providing information for better understanding the mechanism of myopia development [21;22]. Mechanistically, alterations in JNK1 phosphorylation might regulate AQP-1 and CT during the recovery from myopia and the recovery time. Therefore, JNK1 is suggested as a potential therapeutic target for preventing/treating myopia [23].

Myopia and memory:

It is long established that myopia is associated with visual memory [24]. At gene level, RASGRF1 gene locus is associated with both hippocampus-dependent memory [25] and myopia [25;26]. Using a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort, Hysi et al identified a susceptibility locus for refractive error on 15q25 (rs8027411, P = 7.91 × 10⁻⁸). They further replicated this association in 6 adult cohorts of European ancestry with a combined 13,414 persons. Intriguingly, 15q25 locus overlapped the transcription initiation site of RASGRF1 [26]. It is notable that RASGRF1 is highly expressed in retina and neurons and is implicated in retinal function [27] and memory consolidation [25;28]. More crucially, Hysi et al experiment showed that RASGRF1 (-/-) mice present significantly a heavier average crystalline lens.

Chebib et al evaluated effects of cis-3-ACPBPA –which is conformationally restricted analogs of the orally active GABA (B/C) receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742) – on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABA(C) receptor. They showed that cis- and trans-3-ACPBPA when applied to the eye as intravitreal injections in the chick model prevents experimental myopia development and inhibits the associated vitreous chamber elongation in a dose-dependent manner. Interestingly, doses 10 times greater than needed to inhibit recombinant GABA(C) receptors created the anti-myopia effects. More intriguingly, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) when administered intraperitoneally in male Wistar rats, enhanced learning and memory; compared with vehicle there was a statistically significant reduction (p < 0.05; n = 10) in time for rats to find the platform in the Morris water maze task. In short, the memory and refractive effects of CGP36742 may partly be attributed to its GABA(C) activity, suggesting a causal link between myopia-improvement and memory enhancement [29]. It worth to remind that GABA(C) receptors play a role in memory-related disorders [30], myopia [31] and circadian rhythms [32].

As for high hyperopia which is severe form of refractive error, genetic factors are key in its development, however the exact gene responsible for this condition was mostly unknown until very recently. In a large Chinese family with autosomal dominant high hyperopia, Xiao et al [33] using a genome-wide linkage scan mapped the high hyperopia to chromosome 11p12-q13.3, with maximum log of the odds scores of 4.68 at theta = 0 for D11S987. Furthermore, parallel whole-exome sequencing manifested a novel c.3377delG (p.Gly1126Valfs*31) heterozygous mutation in the MYRF gene within the linkage interval. Whole-exome sequencing in other 121 probands with high hyperopia detected other novel mutations in MYRF within two other families: a de novo c.3274_3275delAG (p.Leu1093Profs*22) heterozygous mutation and a c.3194+2T>C heterozygous mutation. It was found that all three mutations are located in the C-terminal region of MYRF and are anticipated to lead in truncation of that portion. Interestingly, two patients from two of the three families developed angle-closure glaucoma. These findings support that truncation mutations in the C-terminal region of MYRF are responsible for autosomal dominant high hyperopia and provide preliminary clues for understanding the functional role of the C-terminal region of this critical myelin regulatory factor, as well as the molecular pathogenesis of high hyperopia and its associated angle-closure glaucoma.

Here, it worth to remind that demyelination is a common pathological characteristic of a large number of neurodegenerative diseases including Huntington's disease (HD) and multiple sclerosis (MS). Yin and colleagues [34] showed that reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin-associated genes, suggesting that PRKG2-regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination

Conclusion:

Collectively, above mentioned findings demonstrate a possible role for AQP1 and AQP4 as common correlates for concurrence of ocular-CNS pathologic pathways.

In this line, particular association between AQP1 [35;36], AQP4 [36;37], and AQP9 [38] with Alzheimer diseases (AD) is well-established. The further elaboration of this idea leads into the involvement of Kir4.1 channel which deserves a separate paper.

Declaration of conflicting interests:

The Author declares that there is no conflict of interest