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BK channels sustain neuronal Ca²⁺ oscillations to support hippocampal long-term potentiation and memory formation.

ABSTRACT: Mutations of large conductance Ca²⁺- and voltage-activated K⁺ channels (BK) are associated with cognitive impairment. Here we report that CA1 pyramidal neuron-specific conditional BK knock-out (cKO) mice display normal locomotor and anxiety behavior. They do, however, exhibit impaired memory acquisition and retrieval in the Morris Water Maze (MWM) when compared to littermate controls (CTRL). In line with cognitive impairment in vivo, electrical and chemical long-term potentiation (LTP) in cKO brain slices were impaired in vitro. We further used a genetically encoded fluorescent K⁺ biosensor and a Ca²⁺-sensitive probe to observe cultured hippocampal neurons during chemical LTP (cLTP) induction. cLTP massively reduced intracellular K⁺ concentration ([K⁺]_i) while elevating L-Type Ca²⁺ channel- and NMDA receptor-dependent Ca²⁺ oscillation frequencies. Both, [K⁺]_i decrease and Ca²⁺ oscillation frequency increase were absent after pharmacological BK inhibition or in cells lacking BK. Our data suggest that L-Type- and NMDAR-dependent BK-mediated K⁺ outflow significantly contributes to hippocampal LTP, as well as learning and memory.

SUBMITTER: Pham T

PROVIDER: S-EPMC10663188 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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BK channels sustain neuronal Ca2+ oscillations to support hippocampal long-term potentiation and memory formation.

Pham Thomas T Hussein Tamara T Calis Dila D Bischof Helmut H Skrabak David D Cruz Santos Melanie M Maier Selina S Spähn David D Kalina Daniel D Simonsig Stefanie S Ehinger Rebekka R Groschup Bernhard B Knipper Marlies M Plesnila Nikolaus N Ruth Peter P Lukowski Robert R Matt Lucas L

Cellular and molecular life sciences : CMLS 20231121 12

Mutations of large conductance Ca2+- and voltage-activated K+ channels (BK) are associated with cognitive impairment. Here we report that CA1 pyramidal neuron-specific conditional BK knock-out (cKO) mice display normal locomotor and anxiety behavior. They do, however, exhibit impaired memory acquisition and retrieval in the Morris Water Maze (MWM) when compared to littermate controls (CTRL). In line with cognitive impairment in vivo, electrical and chemical long-term potent ...[more]

PMID: 37989805

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Project description:Stac protein (named for its SH3- and cysteine-rich domains) was first identified in brain 20 years ago and is currently known to have three isoforms. Stac2, Stac1, and Stac3 transcripts are found at high, modest, and very low levels, respectively, in the cerebellum and forebrain, but their neuronal functions have been little investigated. Here, we tested the effects of Stac proteins on neuronal, high-voltage-activated Ca2+ channels. Overexpression of the three Stac isoforms eliminated Ca2+-dependent inactivation (CDI) of l-type current in rat neonatal hippocampal neurons (sex unknown), but not CDI of non-l-type current. Using heterologous expression in tsA201 cells (together with β and α2-δ1 auxiliary subunits), we found that CDI for CaV1.2 and CaV1.3 (the predominant, neuronal l-type Ca2+ channels) was suppressed by all three Stac isoforms, whereas CDI for the P/Q channel, CaV2.1, was not. For CaV1.2, the inhibition of CDI by the Stac proteins appeared to involve their direct interaction with the channel's C terminus. Within the Stac proteins, a weakly conserved segment containing ∼100 residues and linking the structurally conserved PKC C1 and SH3_1 domains was sufficient to fully suppress CDI. The presence of CDI for l-type current in control neonatal neurons raised the possibility that endogenous Stac levels are low in these neurons and Western blotting indicated that the expression of Stac2 was substantially increased in adult forebrain and cerebellum compared with neonate. Together, our results indicate that one likely function of neuronal Stac proteins is to tune Ca2+ entry via neuronal l-type channels.SIGNIFICANCE STATEMENT Stac protein, first identified 20 years ago in brain, has recently been found to be essential for proper trafficking and function of the skeletal muscle l-type Ca2+ channel and is the site of mutations causing a severe, inherited human myopathy. In neurons, however, functions for Stac protein have remained unexplored. Here, we report that one likely function of neuronal Stac proteins is tuning Ca2+ entry via l-type, but not that via non-l-type, Ca2+ channels. Moreover, there is a large postnatal increase in protein levels of the major neuronal isoform (Stac2) in forebrain and cerebellum, which could provide developmental regulation of l-type channel Ca2+ signaling in these brain regions.

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BK channels sustain neuronal Ca²⁺ oscillations to support hippocampal long-term potentiation and memory formation.

Publications

BK channels sustain neuronal Ca<sup>2+</sup> oscillations to support hippocampal long-term potentiation and memory formation.

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