Modulation of hippocampal excitability via the hydroxycarboxylic acid receptor 1
In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate‐activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the...
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Published in | Hippocampus Vol. 28; no. 8; pp. 557 - 567 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
United States
Wiley Subscription Services, Inc
01.08.2018
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Subjects | |
Online Access | Get full text |
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Summary: | In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate‐activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor‐linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5‐DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4‐CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a Gαi/o‐protein‐coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate. |
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Bibliography: | Funding information Consejo Nacional de Ciencia y Tecnología, México, Grant/Award Numbers: INFR‐2012‐01‐187757, CB‐2016‐281617, 367017 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1050-9631 1098-1063 |
DOI: | 10.1002/hipo.22958 |