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H2 histamine receptor-phosphorylation of Kv3.2 modulates interneuron fast spiking

Abstract

Histamine-containing neurons of the tuberomammilary nucleus project to the hippocampal formation to innervate H1 and H2 receptors on both principal and inhibitory interneurons. Here we show that H2 receptor activation negatively modulates outward currents through Kv3.2-containing potassium channels by a mechanism involving PKA phosphorylation in inhibitory interneurons. PKA phosphorylation of Kv3.2 lowered the maximum firing frequency of inhibitory neurons, which in turn negatively modulated high-frequency population oscillations recorded in principal cell layers. All these effects were absent in a Kv3.2 knockout mouse. These data reveal a novel pathway for histamine-dependent regulation of high-frequency oscillations within the hippocampal formation.

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Figure 1: Kv3.2 is expressed in parvalbumin- and a subpopulation of somatostatin-containing hippocampal interneurons.
Figure 2: Sustained outward K+ currents resembling Kv3.2 currents are modulated by H2 receptor activation and db-cAMP in interneurons.
Figure 3: TEA, H2 agonists and PKA activation modulate the same outward current.
Figure 4: H2 agonist and PKA modulation of outward currents are absent in interneurons from Kv3.2 mutant hippocampus, but block by TEA is normal.
Figure 5: Dentate gyrus interneurons but not CA3 pyramidal neurons sustain high action-potential firing frequencies.
Figure 6: H2 receptor- and PKA-modulation of interneuron firing frequency is absent in the Kv3.2 knockout mouse.
Figure 7: PKA phosphorylation of Kv3.2 reduces the incidence of high-frequency oscillations in CA3.

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Acknowledgements

The authors thank V. Gallo and J. Lawrence for constructive criticism of the manuscript and K. Toth for advice throughout the study. B.R. was supported by NIH NS30989 and NS35215.

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Correspondence to Chris J. McBain.

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Atzori, M., Lau, D., Tansey, E. et al. H2 histamine receptor-phosphorylation of Kv3.2 modulates interneuron fast spiking. Nat Neurosci 3, 791–798 (2000). https://doi.org/10.1038/77693

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