Abstract
Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4-null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4-null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory.
Highlights
Astrocytes were previously thought to act only as support cells, over the years, increasing amount of evidence have implicated more dynamic functions of these glial cells (Volterra and Meldolesi, 2005)
It is clear that the absence of AQP4 plays a unique role in synaptic plasticity and learning and memory the exact mechanisms remain unclear
The fundamental basis of long term potentiation (LTP) induction requires NMDA receptor (NMDAR) activation, mechanisms underlying the impairment of LTP in AQP4null mice seems to be an indirect consequence from the lack of AQP4
Summary
Astrocytes were previously thought to act only as support cells, over the years, increasing amount of evidence have implicated more dynamic functions of these glial cells (Volterra and Meldolesi, 2005). The traditional view of excess brain water elimination is believed to be through the bulk flow of fluid through the extracellular space (ECS) and the glial limitans, into the ventricles, and eventually into the blood through AQP4 located at the astrocytic endfeet (Verkman et al, 2006; Smith et al, 2015) This theory is supported by studies using models of brain edema and ischemia where electron microscopy findings demonstrate endfeet swelling of astrocytes suggesting AQP4-dependent mediated osmotic water uptake (Manley et al, 2000; Ito et al, 2011) and early induction of AQP4 reduced the development of edema formation (Hirt et al, 2009). Mice lacking AQP4 exhibited faster ECS diffusion than WT suggesting an ECS expansion (Binder et al, 2004b) Compelling evidence from these studies show that AQP4 control water and ion homeostasis and plays a role in neural signal conduction that may potentially contribute to synaptic transmission that is regulated by water transport.
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