KIBRA anchoring the action of PKMζ maintains the persistence of memory

Tsokas, Panayiotis; Hsieh, Changchi; Flores-Obando, Rafael E.; Bernabo, Matteo; Tcherepanov, Andrew; Hernández, A. Iván; Thomas, Christian; Bergold, Peter J.; Cottrell, James E.; Kremerskothen, Joachim; Shouval, Harel Z.; Nader, Karim; Fenton, André A.; Sacktor, Todd C.

doi:10.1126/sciadv.adl0030

Cited by 4 publications

References 87 publications

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Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical PKC in the anterior cingulate cortex

Almaguer-Melian,

Mercerón-Martínez,

Alacán-Ricardo

et al. 2024

Preprint

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Although many studies have addressed the role of the amygdala in modulating long-term memory, it is not known whether weak training plus amygdala stimulation can transform a short-term memory into a remote memory. Object place recognition (OPR) memory after strong training remains hippocampus-dependent through the persistent action of PKMζ for at least 6 days, but it is unknown whether weak training plus amygdala stimulation can transform short-term memory into an even longer memory, and whether such memory is stored through more persistent action of PKMζ in hippocampus. We trained rats to acquire OPR and 15 min or 5 h later induced a brief pattern of electrical stimulation in basolateral amygdala (BLA). Our results reveal that a short-term memory lasting < 4 h can be converted into remote memory lasting at least 3 weeks if the BLA is activated 15 min, but not 5 h after learning. To examine how this remote memory is maintained, we injected ZIP, an inhibitor of atypical PKCs (aPKCs), PKMζ and PKCι/λ, into either hippocampal CA1, dentate gyrus (DG), or anterior cingulate cortex (ACC). Our data reveal amygdala stimulation produces consolidation into remote memory, not by persistent aPKC activation and capture by synaptic tagging processes in the hippocampal formation, but in ACC. Our data establish a powerful modulating role of the BLA in forming remote memory and open a path in the search for neurological restoration of memory, based on enhancing synaptic plasticity in aging or neurodegenerative disorders such as Alzheimer's disease.

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Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical PKC in the anterior cingulate cortex

Almaguer-Melian,

Mercerón-Martínez,

Alacán-Ricardo

et al. 2024

Preprint

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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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Maintenance of synaptic plasticity by negative-feedback of synaptic protein elimination: Dynamic modeling of KIBRA-PKMζ interactions in LTP and memory

Shouval,

Flores-Obando,

Sacktor

2024

Preprint

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Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Current theories propose that the long-term maintenance of synaptic efficacies and memory is accomplished via a positive-feedback loop at the level of production of a protein species or a protein state. Here we propose a qualitatively different theoretical framework based on negative-feedback at the level of protein elimination. This theory is motivated by recent experimental findings regarding the binding of PKMζ and KIBRA, two synaptic proteins involved in maintenance of memory, and on how this binding affects the proteins' degradation. We demonstrate this theoretical framework with two different models, a simple abstract model to explore generic features of such a process, and an experimentally motivated phenomenological model. The results of these models are qualitatively consistent with existing data, and generate novel predictions that could be experimentally tested to further validate or reject the negative-feedback theory.

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KIBRA anchoring the action of PKMζ maintains the persistence of memory

Cited by 4 publications

References 87 publications

Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical PKC in the anterior cingulate cortex

Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical PKC in the anterior cingulate cortex

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

Maintenance of synaptic plasticity by negative-feedback of synaptic protein elimination: Dynamic modeling of KIBRA-PKMζ interactions in LTP and memory

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