The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage.

/pdf/aquaporin-water-channels-in-the-nervous-system-3y7qn0u058.pdf

Aquaporin water channels in the nervous system

Aquaporin-4 (AQP4) is one of the most abundant molecules in the brain and is particularly prevalent in astrocytic membranes at the blood-brain and brain-liquor interfaces. While AQP4 has been implicated in a number of pathophysiological processes, its role in brain physiology has remained elusive. Only recently has evidence accumulated to suggest that AQP4 is involved in such diverse functions as regulation of extracellular space volume, potassium buffering, cerebrospinal fluid circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, and Ca2+ signaling. AQP4 is also required for normal function of the retina, inner ear, and olfactory system. A review will be provided of the physiological roles of AQP4 in brain and of the growing list of data that emphasize the polarized nature of astrocytes.

Physiological Roles of Aquaporin-4 in Brain

Preventing or reducing amyloid-beta (Aβ) accumulation in the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Aβ clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent. Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12-moth old APP/PS1 mice, with increases in Aβ accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignficant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples. These results suggest that AQP4 attenuates Aβ pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD.

/pdf/deletion-of-aquaporin-4-in-app-ps1-mice-exacerbates-brain-ab-2k2o8vcb4r.pdf

Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits

The brain has high-order functions and is composed of several kinds of cells, such as neurons and glial cells. It is becoming clear that many kinds of neurodegenerative diseases are more-or-less influenced by astrocytes, which are a type of glial cell. Aquaporin-4 (AQP4), a membrane-bound protein that regulates water permeability is a member of the aquaporin family of water channel proteins that is expressed in the endfeet of astrocytes in the central nervous system (CNS). Recently, AQP4 has been shown to function, not only as a water channel protein, but also as an adhesion molecule that is involved in cell migration and neuroexcitation, synaptic plasticity, and learning/memory through mechanisms involved in long-term potentiation or long-term depression. The most extensively examined role of AQP4 is its ability to act as a neuroimmunological inducer. Previously, we showed that AQP4 plays an important role in neuroimmunological functions in injured mouse brain in concert with the proinflammatory inducer osteopontin (OPN). The aim of this review is to summarize the functional implication of AQP4, focusing especially on its neuroimmunological roles. This review is a good opportunity to compile recent knowledge and could contribute to the therapeutic treatment of autoimmune diseases through strategies targeting AQP4. Finally, the author would like to hypothesize on AQP4’s role in interaction between reactive astrocytes and reactive microglial cells, which might occur in neurodegenerative diseases. Furthermore, a therapeutic strategy for AQP4-related neurodegenerative diseases is proposed.

Neuroimmunological Implications of AQP4 in Astrocytes

Regulation of astrocyte glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) expression in a model of epilepsy.

Aquaporin-4 (AQP4), the most abundant aquaporin in the brain, is polarized at the glial end-feet facing peri-synaptic areas. AQP4 has been hypothesized to modulate water and potassium fluxes associated with neuronal activity in pathophysiological states. However, the role of AQP4 in astroglial signaling under physiological conditions is unclear. Herein, AQP4 knockout mice and wild-type littermates were tested in the Morris water maze (MWM), which allows for investigating the role of AQP4 in long-term learning and memory. Compared with wild-type mice, AQP4 knockout mice appeared actually to find the platform more easy, but to forget more quickly, in the MWM, indicating that AQP4 knockout mice exhibited impaired memory consolidation in MWM. Moreover, the deficits of memory consolidations were associated with defects in theta-burst stimulation-induced long-term potentiation both in vivo and in vitro. Furthermore, AQP4 knockout mice were accompanied by a decrease in the incorporation of adult-generated granule cells into spatial memory networks. Taken together, our findings indicate that AQP4 plays a modulatory role in memory consolidation. Targeting glial AQP4 may be a new therapeutic strategy for neurodegenerative disorders and related memory impairment.

Aquaporin-4 promotes memory consolidation in Morris water maze

Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting long-term potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 μM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist (CGRP8-37 ), N-methyl-d-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl-d-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. Calcitonin gene-related peptide (CGRP) plays an essential role in synaptic plasticity in the amygdala and fear memory. We found that CGRP-induced chemical long-term potentiation (LTP) in a dose-dependent way in the BLA-CeA (basolateral and central nucleus of amygdala, respectively) pathway and enhanced fear memory extinction in rats through a protein kinase A (PKA)-dependent postsynaptic mechanism that involved NMDA receptors. These results support a pivotal role of CGRP in amygdala.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13246

Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats.

Aquaporin-4 deficiency facilitates fear memory extinction in the hippocampus through excessive activation of extrasynaptic GluN2B-containing NMDA receptors

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Aquaporin-4 promotes memory consolidation in Morris water maze

Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats.

Aquaporin-4 deficiency facilitates fear memory extinction in the hippocampus through excessive activation of extrasynaptic GluN2B-containing NMDA receptors