Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus

Center for Glial-Neuronal Interactions, Division of Biomedical Sciences, 1247 Webber Hall, University of California, Riverside, CA 92521, USA.
Neuroscience (Impact Factor: 3.36). 03/2011; 178:21-32. DOI: 10.1016/j.neuroscience.2011.01.020
Source: PubMed


Mice deficient in the water channel aquaporin-4 (AQP4) demonstrate increased seizure duration in response to hippocampal stimulation as well as impaired extracellular K+ clearance. However, the expression of AQP4 in the hippocampus is not well described. In this study, we investigated (i) the developmental, laminar and cell-type specificity of AQP4 expression in the hippocampus; (ii) the effect of Kir4.1 deletion on AQP4 expression; and (iii) performed Western blot and RT-PCR analyses. AQP4 immunohistochemistry on coronal sections from wild-type (WT) or Kir4.1-/- mice revealed a developmentally-regulated and laminar-specific pattern, with highest expression in the CA1 stratum lacunosum-moleculare (SLM) and the molecular layer (ML) of the dentate gyrus (DG). AQP4 was colocalized with the glial markers glial fibrillary acidic protein (GFAP) and S100β in the hippocampus, and was also ubiquitously expressed on astrocytic endfeet around blood vessels. No difference in AQP4 immunoreactivity was observed in Kir4.1-/- mice. Electrophysiological and postrecording RT-PCR analyses of individual cells revealed that AQP4 and Kir4.1 were co-expressed in nearly all CA1 astrocytes. In NG2 cells, AQP4 was also expressed at the transcript level. This study is the first to examine subregional AQP4 expression during development of the hippocampus. The strikingly high expression of AQP4 in the CA1 SLM and DG ML identifies these regions as potential sites of astrocytic K+ and H2O regulation. These results begin to delineate the functional capabilities of hippocampal subregions and cell types for K+ and H2O homeostasis, which is critical to excitability and serves as a potential target for modulation in diverse diseases.

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Available from: Devin K Binder, Dec 10, 2014
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    • "The IHC-o identifies a characteristic staining pattern that corresponds well to the anatomical distribution of AQP4 in the brain [18]. The pattern is well recognized despite the presence of other antibodies (e.g. "
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    ABSTRACT: Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.
    PLoS ONE 11/2013; 8(11):e79083. DOI:10.1371/journal.pone.0079083 · 3.23 Impact Factor
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    • "Research with transgenic AQP4 knockout mice support this hypothesis as they have increased ECS volume and are less susceptible to PTZ-induced seizures (Binder et al., 2004a,b). Glial-mediated water flow is also tightly coupled to K+ transport from the ECS through the inward rectifying K+ channel, Kir4.1, that is colocalized with AQP4 on the astrocyte membrane (Hsu et al., 2011). Similar to ECS volume, changes in the K+ concentration influence neuronal excitability with millimolar increases in ECS K+ exacerbating epileptiform activity (Feng and Durand, 2006). "
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    ABSTRACT: Neuronal excitability of the brain and ongoing homeostasis depend not only on intrinsic neuronal properties, but also on external environmental factors; together these determine the functionality of neuronal networks. Homeostatic factors become critically important during epileptogenesis, a process that involves complex disruption of self-regulatory mechanisms. Here we focus on the bioenergetic homeostatic network regulator adenosine, a purine nucleoside whose availability is largely regulated by astrocytes. Endogenous adenosine modulates complex network function through multiple mechanisms including adenosine receptor-mediated pathways, mitochondrial bioenergetics, and adenosine receptor-independent changes to the epigenome. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Conversely, we have found that reconstruction of adenosine's homeostatic functions provides new hope for the prevention of epileptogenesis. We will discuss how adenosine-based therapeutic approaches may interfere with epileptogenesis on an epigenetic level, and how dietary interventions can be used to restore network homeostasis in the brain. We conclude that reconstruction of homeostatic functions in the brain offers a new conceptual advance for the treatment of neurological conditions which goes far beyond current target-centric treatment approaches.
    Frontiers in Cellular Neuroscience 07/2013; 7:109. DOI:10.3389/fncel.2013.00109 · 4.29 Impact Factor
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    • "Astrocytes mediate the redistribution of water, using AQP4 to facilitate glial water uptake at sites of neuronal activation and water efflux at distant sites (Nagelhus et al., 2004; Nielsen et al., 1997). The distribution of AQP4 in the hippocampus and its regulation and role in epileptogenesis have recently been investigated and extensively reviewed (Binder et al., 2012; Hsu et al., 2011; Lee et al., 2012). Increased water content in the sclerotic human hippocampus was first suggested by an increased T2-weighted signal and decreased T1-weighted signal in magnetic resonance imaging (Mitchell et al., 1999); this was later confirmed with a higher diffusion coefficient in diffusion weighted imaging (Hugg et al., 1999; Lee et al., 2004). "
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    ABSTRACT: It is estimated that one in 26 people will develop epilepsy in their lifetime, amounting to almost 12 million people in the United States alone (Hesdorffer et al., 2011). Epilepsy is a group of conditions characterized by sporadic occurrence of seizures and unconsciousness. This severely limits the ability to perform everyday tasks and leads to increased difficulty with learning and memory, maintenance of steady employment, driving, and overall socioeconomic integration. A greater understanding of the cellular and molecular mechanisms underlying seizures and epilepsy is necessary, as it may lead to novel antiepileptic treatments. In this chapter, we will review the current literature surrounding the involvement of glial cells in epilepsy with particular emphasis on review of human tissue studies and some possible underlying mechanisms. Based on the current evidence and hypotheses of glial mechanisms in epilepsy, novel therapeutic opportunities for the treatment of epilepsy will also be presented.
    Neurochemistry International 01/2013; 63(7). DOI:10.1016/j.neuint.2013.01.017 · 3.09 Impact Factor
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