O24: Brainstem astrocyte Kir4.1 potassium channel expression in the rat TgF344-AD model of Alzheimer's disease

Froggett, Poppy, Hussan, Sanawor, Allan, Stuart, Greenstein, Adam, Robinson, Andrew, Gigg, John and Hawkins, Virginia ORCID: https://orcid.org/0000-0001-9505-6776 (2023) O24: Brainstem astrocyte Kir4.1 potassium channel expression in the rat TgF344-AD model of Alzheimer's disease. In: Summer Meeting of the Anatomical Society: Dublin 2022, 4th July 2022 - 6th July 2022, Dublin, Republic of Ireland.

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Abstract

The retrotrapezoid nucleus (RTN) is a key brainstem locus for central respiratory control. Chemosensitive neurons in the RTN have been shown to be intrinsically sensitive to changes in CO2/H+ and to regulate breathing in a CO2/H+-dependent manner. However, astroglial cells also contribute to RTN chemoreception by providing a CO2/H+-dependent purinergic drive that enhances neural activity, likely via a mechanism involving the inhibition of Kir4.1 channels. We recently found that an inducible astroglial cell-specific Kir4.1 potassium channel knockout mouse had reduced breathing responses to hypercapnic conditions, demonstrating that Kir4.1 channels are important mediators of central chemoreception and respiratory control. Kir4.1 expression or activity in animal models has also been shown to be reduced in various pathological conditions including epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, respiratory dysfunction has been implicated in the progression of such neurodegenerative disorders. We assessed respiratory brainstem Kir4.1 expression levels using immunohistochemistry and qPCR in both young adult (2–3 months) and aged (9 months) rodent AD transgenic model tissue. Our preliminary findings show Kir4.1 expression levels in astrocytes (Aldh1L1+ astroglial cells) were significantly higher in the RTN compared to hippocampal regions, as well as being significantly increased in aged tissue. Interestingly, Kir4.1 levels were consistently greater in female tissue compared to male tissue. Furthermore, astrocyte Kir4.1 expression levels were lower in aged TgF344-AD RTN tissue than in TgF344-WT controls. These findings did not appear to be restricted to cell bodies as preliminary data suggests Kir4.1 expression is also reduced at perivascular astrocyte end feet in the TgF344-AD RTN. This data demonstrates that altered Kir4.1 expression in neurodegenerative disease is not restricted to upper brain regions but may also be apparent in brainstem respiratory nuclei where it is involved in chemosensation and ventilatory drive. This supports the hypothesis that astrocyte contributions to respiratory control may become compromised with age, in a manner that leads to respiratory dysfunction in neurodegenerative disorders. Full institutional ethical approval was obtained from Manchester Metropolitan University, and all procedures were carried out in accordance with the Animals (Scientific Procedures) Act, 1986. Funded by Manchester Academic Health Science Centre.