Critical role of aquaporin-4 (AQP4) in astrocytic Ca ²⁺ signaling events elicited by cerebral edema

Abstract

Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca 2+ signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo twophoton imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca 2+ spikes and that deletion of Aqp4 reduces these signals. The Ca 2+ signals are partly dependent on activation of P2 purinergic receptors, which was judged from the effects of appropriate antagonists applied to cortical slices. Supporting the involvement of purinergic signaling, osmotic stress was found to induce ATP release from cultured astrocytes in an AQP4-dependent manner. Our results suggest that AQP4 not only serves as an influx route for water but also is critical for initiating downstream signaling events that may affect and potentially exacerbate the pathological outcome in clinical conditions associated with brain edema.endfeet | glial | two-photon

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

“…Sadly, the costs associated with its consequences and, often, futile treatments [31][32][33] , which have remained unchanged in almost a century, put immense economic burden on families and society in general. One of the key mediators of increased ICP is a dramatic shift in water diffusion across the BBB 4,34 .…”

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

“…Aquaporin-4 (AQP4), a predominant water channel in adult brain, is widely expressed in astrocytes (Nielsen et al, 1997) and plays important roles in the regulation of extravascular brain water, brain volume homeostasis, and cerebrospinal fluid production (AmiryMoghaddam and Ottersen, 2003). A lot of evidence shows that AQP4 is involved in the pathophysiology of cerebral disorders, including stroke, cerebral edema, traumatic brain injury, Parkinson's disease, epilepsy, and depression, and so on (Binder et al, 2006;Chi et al, 2011;Ding et al, 2009;Friedman et al, 2009;Kong et al, 2009;Thrane et al, 2011). Recent studies demonstrate that AQP4 knockout (KO) inhibits the formation of glial cell-derived neurotrophic factor and increases microglial inflammatory responses in MPTP-treated mouse model of Parkinson's disease (Chi et al, 2011;Fan et al, 2008).…”

TRPV4-AQP4 interactions ‘turbocharge’ astroglial sensitivity to small osmotic gradients

“…2,4,5 We hypothesize that coordination of activitydependent ionic/water fluxes at the blood-retina barrier critically depends on functional interactions between endfoot TRPV4, AQP4 and Kir4.1 channels. This osmoregulatory complex links changes in glial water permeability, K C uptake, ATP release and Ca 2C homeostasis that occur in response to during neuronal firing, 1,8 to downstream modulation of Aqp4 and Kcnj10 and astroglial function by maintaining the steady-state 'osmo-tensile' homeostasis. In the presence of prolonged osmotic stress or pathological circumstances (such as diabetes, traumatic ocular injury or glaucoma), however, TRPV4-AQP4 interactions associated with excessive swelling of CNS astroglia 'turbo-charge' inflammatory remodeling through deranged Ca 2C signaling, reactive gliosis and macular or brain edema.…”