Reduced activity of GIRK1-containing heterotetramers is sufficient to affect neuronal functions, including synaptic plasticity and spatial learning and memory

Alice Mett; Izhar Karbat; Michael Tsoory; Shachar Fine; Shachar Iwanir; Eitan Reuveny

doi:10.1113/JP280434

Reduced activity of GIRK1-containing heterotetramers is sufficient to affect neuronal functions, including synaptic plasticity and spatial learning and memory

Alice Mett, Izhar Karbat, Michael Tsoory, Shachar Fine, Shachar Iwanir, Eitan Reuveny^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

GIRK channels are essential for the slow inhibition of electrical activity in the nervous system and heart rate regulation via the parasympathetic system. The implications of individual GIRK isoforms in specific physiological activities are based primarily on studies conducted with GIRK‐null mouse lines. Here we utilize a novel knockin mouse line in which YFP was fused in‐frame to the N‐terminus of GIRK1 (YFP‐GIRK1) to correlate GIRK1 spatial distribution with physiological activities. These mice, however, displayed spontaneous seizure‐like activity and thus were investigated for the origin of such activity. We show that GIRK tetramers containing YFP‐GIRK1 are correctly assembled and trafficked to the plasma membrane, but are functionally impaired. A battery of behavioural assays conducted on YFP‐GIRK1 and GIRK1‐null (GIRK1−/−) mice revealed similar phenotypes, including impaired nociception, reduced anxiety and hyperactivity in an unfamiliar environment. However, YFP‐GIRK1 mice exhibited increased home‐cage locomotion while GIRK1−/− mice did not. In addition, we show that the GIRK1 subunit is essential for intact spatial learning and memory and synaptic plasticity in hippocampal brain slices. This study expands our knowledge regarding the role of GIRK1 in neuronal processes and underlines the importance of GIRK1‐containing heterotetramers.

Original language	English
Pages (from-to)	521-545
Number of pages	25
Journal	Journal of Physiology
Volume	599
Issue number	2
Early online date	21 Nov 2020
DOIs	https://doi.org/10.1113/JP280434
Publication status	Published - 15 Jan 2021

Funding

We thank Professor Kevin Wickman for kindly providing the GIRK1−/− mouse line. This study was supported, in part, by The Israel Science Foundation Grant Number 1248/15, the Minerva Foundation, the Willner Family Fund and the NIH Ruth L. Kirschstein National Research Service Award F05‐NS059232 (to E.R.). M.T. is the incumbent of the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases. E.R. is the incumbent of the Charles H. Hollenberg Professorial Chair and the Director of the David Barton Centre for Research on the Chemistry of Life. Author cotributions - All authors contributed to the conception and design of the work, acquisition, analysis and interpretation, drafting the work or revising it critically for important intellectual content. All authors approved the final version of the article and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

All Science Journal Classification (ASJC) codes

Physiology

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10.1113/JP280434

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title = "Reduced activity of GIRK1-containing heterotetramers is sufficient to affect neuronal functions, including synaptic plasticity and spatial learning and memory",

abstract = "GIRK channels are essential for the slow inhibition of electrical activity in the nervous system and heart rate regulation via the parasympathetic system. The implications of individual GIRK isoforms in specific physiological activities are based primarily on studies conducted with GIRK‐null mouse lines. Here we utilize a novel knockin mouse line in which YFP was fused in‐frame to the N‐terminus of GIRK1 (YFP‐GIRK1) to correlate GIRK1 spatial distribution with physiological activities. These mice, however, displayed spontaneous seizure‐like activity and thus were investigated for the origin of such activity. We show that GIRK tetramers containing YFP‐GIRK1 are correctly assembled and trafficked to the plasma membrane, but are functionally impaired. A battery of behavioural assays conducted on YFP‐GIRK1 and GIRK1‐null (GIRK1−/−) mice revealed similar phenotypes, including impaired nociception, reduced anxiety and hyperactivity in an unfamiliar environment. However, YFP‐GIRK1 mice exhibited increased home‐cage locomotion while GIRK1−/− mice did not. In addition, we show that the GIRK1 subunit is essential for intact spatial learning and memory and synaptic plasticity in hippocampal brain slices. This study expands our knowledge regarding the role of GIRK1 in neuronal processes and underlines the importance of GIRK1‐containing heterotetramers.",

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AU - Fine, Shachar

AU - Iwanir, Shachar

AU - Reuveny, Eitan

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N2 - GIRK channels are essential for the slow inhibition of electrical activity in the nervous system and heart rate regulation via the parasympathetic system. The implications of individual GIRK isoforms in specific physiological activities are based primarily on studies conducted with GIRK‐null mouse lines. Here we utilize a novel knockin mouse line in which YFP was fused in‐frame to the N‐terminus of GIRK1 (YFP‐GIRK1) to correlate GIRK1 spatial distribution with physiological activities. These mice, however, displayed spontaneous seizure‐like activity and thus were investigated for the origin of such activity. We show that GIRK tetramers containing YFP‐GIRK1 are correctly assembled and trafficked to the plasma membrane, but are functionally impaired. A battery of behavioural assays conducted on YFP‐GIRK1 and GIRK1‐null (GIRK1−/−) mice revealed similar phenotypes, including impaired nociception, reduced anxiety and hyperactivity in an unfamiliar environment. However, YFP‐GIRK1 mice exhibited increased home‐cage locomotion while GIRK1−/− mice did not. In addition, we show that the GIRK1 subunit is essential for intact spatial learning and memory and synaptic plasticity in hippocampal brain slices. This study expands our knowledge regarding the role of GIRK1 in neuronal processes and underlines the importance of GIRK1‐containing heterotetramers.

AB - GIRK channels are essential for the slow inhibition of electrical activity in the nervous system and heart rate regulation via the parasympathetic system. The implications of individual GIRK isoforms in specific physiological activities are based primarily on studies conducted with GIRK‐null mouse lines. Here we utilize a novel knockin mouse line in which YFP was fused in‐frame to the N‐terminus of GIRK1 (YFP‐GIRK1) to correlate GIRK1 spatial distribution with physiological activities. These mice, however, displayed spontaneous seizure‐like activity and thus were investigated for the origin of such activity. We show that GIRK tetramers containing YFP‐GIRK1 are correctly assembled and trafficked to the plasma membrane, but are functionally impaired. A battery of behavioural assays conducted on YFP‐GIRK1 and GIRK1‐null (GIRK1−/−) mice revealed similar phenotypes, including impaired nociception, reduced anxiety and hyperactivity in an unfamiliar environment. However, YFP‐GIRK1 mice exhibited increased home‐cage locomotion while GIRK1−/− mice did not. In addition, we show that the GIRK1 subunit is essential for intact spatial learning and memory and synaptic plasticity in hippocampal brain slices. This study expands our knowledge regarding the role of GIRK1 in neuronal processes and underlines the importance of GIRK1‐containing heterotetramers.

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Reduced activity of GIRK1-containing heterotetramers is sufficient to affect neuronal functions, including synaptic plasticity and spatial learning and memory

Abstract

Funding

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