KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Kauwe, Grant; Pareja-Navarro, Kristeen A.; Yao, Lei; Chen, Jackson H.; Wong, Ivy; Saloner, Rowan; Cifuentes, Helen; Nana, Alissa L.; Shah, Samah; Li, Yaqiao; Le, David; Spina, Salvatore; Grinberg, Lea T.; Seeley, William W.; Kramer, Joel H.; Sacktor, Todd C.; Schilling, Birgit; Gan, Li; Casaletto, Kaitlin B.; Tracy, Tara E.

doi:10.1172/jci169064

Cited by 3 publications

References 81 publications

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Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice

Nikulina,

Tsokas,

Whitney

et al. 2024

Preprint

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Cognitive deficits frequently arise after traumatic brain injury. The murine closed head injury (CHI) models these deficits since injured mice cannot acquire Barnes maze. Dosing of minocycline plus N-acetylcysteine beginning 12 hours post-CHI (MN12) restores Barnes maze acquisition by an unknown mechanism. Increased hippocampal synaptic efficacy is needed to acquire Barnes maze, synaptic long-term potentiation (LTP) models this increased synaptic efficacy in vitro. LTP has an early phase (E-LTP) lasting up to one hour that is mediated by second messengers that is followed by a late phase (L-LTP) that needs new synthesis of protein kinase M zeta (PKMζ). PKMζ has constitutive kinase activity because it lacks the autoinhibitory regulatory domain found in other PKCs. Due to its constitutive activity, the amount of PKMζ kinase activity is determined by PKMz protein levels. We report that CHI bilaterally decreases PKMζ levels in the CA3 and CA1 hippocampus. MN12 increases CA1 PKMζ expression. CHI inhibits E-LTP in slices from the ipsilesional hippocampus and inhibits L-LTP in slices from both hippocamppi. MN12 treatment reestablishes both E-LTP and L-LTP in slices from the injured MN12-treated hippocampus. The restoration of L-LTP from injured MN12-treated hippocampus is mediated by PKMζ because L-LTP is blocked by the specific PKMζ inhibitor, ζ-stat. Hippocampal ζ-stat infusions also prevent Barnes maze acquisition in injured, MN12-treated mice. These data suggest that post-injury minocycline plus N-acetylcysteine targets PKMζ to improve synaptic plasticity and cognition in mice with closed-head injury.

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Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice

Nikulina,

Tsokas,

Whitney

et al. 2024

Preprint

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KIBRA anchoring the action of PKMζ maintains the persistence of memory

Tsokas,

Hsieh,

Flores-Obando

et al. 2024

Sci. Adv.

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How can short-lived molecules selectively maintain the potentiation of activated synapses to sustain long-term memory? Here, we find kidney and brain expressed adaptor protein (KIBRA), a postsynaptic scaffolding protein genetically linked to human memory performance, complexes with protein kinase Mzeta (PKMζ), anchoring the kinase’s potentiating action to maintain late-phase long-term potentiation (late-LTP) at activated synapses. Two structurally distinct antagonists of KIBRA-PKMζ dimerization disrupt established late-LTP and long-term spatial memory, yet neither measurably affects basal synaptic transmission. Neither antagonist affects PKMζ-independent LTP or memory that are maintained by compensating PKCs in ζ-knockout mice; thus, both agents require PKMζ for their effect. KIBRA-PKMζ complexes maintain 1-month-old memory despite PKMζ turnover. Therefore, it is not PKMζ alone, nor KIBRA alone, but the continual interaction between the two that maintains late-LTP and long-term memory.

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Extreme value statistics of nerve transmission delay

Tsuzuki

2024

PLoS ONE

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Delays in nerve transmission are an important topic in the field of neuroscience. Spike signals fired or received by the dendrites of a neuron travel from the axon to a presynaptic cell. The spike signal then triggers a chemical reaction at the synapse, wherein a presynaptic cell transfers neurotransmitters to the postsynaptic cell, regenerates electrical signals via a chemical reaction through ion channels, and transmits them to neighboring neurons. In the context of describing the complex physiological reaction process as a stochastic process, this study aimed to show that the distribution of the maximum time interval of spike signals follows extreme-order statistics. By considering the statistical variance in the time constant of the leaky Integrate-and-Fire model, a deterministic time evolution model for spike signals, we enabled randomness in the time interval of the spike signals. When the time constant follows an exponential distribution function, the time interval of the spike signal also follows an exponential distribution. In this case, our theory and simulations confirmed that the histogram of the maximum time interval follows the Gumbel distribution, one of the three forms of extreme-value statistics. We further confirmed that the histogram of the maximum time interval followed a Fréchet distribution when the time interval of the spike signal followed a Pareto distribution. These findings confirm that nerve transmission delay can be described using extreme value statistics and can therefore be used as a new indicator of transmission delay.

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KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Cited by 3 publications

References 81 publications

Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice

Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice

KIBRA anchoring the action of PKMζ maintains the persistence of memory

Extreme value statistics of nerve transmission delay

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