20 research outputs found
Erasing Sensorimotor Memories via PKMĪ¶ Inhibition
Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMĪ¶). Whereas the role of PKMĪ¶ in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMĪ¶ inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training. The rate of relearning the task after the memory disruption by ZIP was indistinguishable from the rate of initial learning, suggesting no significant savings after the memory loss. These results indicate a shared molecular mechanism of storage for declarative and procedural forms of memory
What does LTP tell us about the roles of CaMKII and PKMĪ¶ in memory?
Abstract In āCriteria for identifying the molecular basis of the engram (CaMKII, PKMĪ¶),ā Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMĪ¶ as memory storage molecules: necessity, occlusion, and erasure. Here we show that when the criteria are tested, the results reveal important differences between the molecules. Inhibiting PKMĪ¶ reverses established, protein synthesis-dependent late-LTP, without affecting early-LTP or baseline synaptic transmission. In contrast, blocking CaMKII has two effects: 1) inhibiting CaMKII activity blocks LTP induction but not maintenance, and 2) disrupting CaMKII interactions with NMDARs in the postsynaptic density (PSD) depresses both early-LTP and basal synaptic transmission equivalently. To identify a maintenance mechanism, we propose a fourth criterion ā persistence. PKMĪ¶ increases for hours during LTP maintenance in hippocampal slices, and for over a month in specific brain regions during long-term memory storage in conditioned animals. In contrast, increased CaMKII activity lasts only minutes following LTP induction, and CaMKII translocation to the PSD in late-LTP or memory has not been reported. Lastly, do the PKMĪ¶ and CaMKII models integrate the many other signaling molecules important for LTP? Activity-dependent PKMĪ¶ synthesis is regulated by many of the signaling molecules that induce LTP, including CaMKII, providing a plausible mechanism for new gene expression in the persistent phosphorylation by PKMĪ¶ maintaining late-LTP and memory. In contrast, CaMKII autophosphorylation and translocation do not appear to require new protein synthesis. Therefore, the cumulative evidence supports a core role for PKMĪ¶ in late-LTP and long-term memory maintenance, and separate roles for CaMKII in LTP induction and for the maintenance of postsynaptic structure and synaptic transmission in a mechanism distinct from late-LTP
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The genetics of PKMĪ¶ and memory maintenance
Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase MĪ¶ (PKMĪ¶) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMĪ¶ has been challenged by genetic data from PKMĪ¶-knockout mice showing intact LTP and long-term memory. Moreover, the PKMĪ¶ inhibitor peptide Ī¶ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMĪ¶-antisense approach showed that LTP and long-term memory in PKMĪ¶-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCĪ¹/Ī». Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCĪ¹/Ī» knockdown disrupted short-term memory, whereas PKMĪ¶ knockdown specifically erased long-term memory. Third, conditional PKCĪ¹/Ī» knockout induced compensation by rapidly activating PKMĪ¶ to preserve short-term memory. Fourth, a dominant-negative approach in the model system Aplysia revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMĪ¶ is the principal PKC isoform that maintains LTP and long-term memory. PKCĪ¹/Ī» can compensate for PKMĪ¶, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMĪ¶ malfunctions
Protein kinase MĪ¶ is essential for the induction and maintenance of dopamine-induced long-term potentiation in apical CA1 dendrites
Dopaminergic D1/D5-receptor-mediated processes are important for certain forms of memory as well as for a cellular model of memory, hippocampal long-term potentiation (LTP) in the CA1 region of the hippocampus. D1/D5-receptor function is required for the induction of the protein synthesis-dependent maintenance of CA1-LTP (L-LTP) through activation of the cAMP/PKA-pathway. In earlier studies we had reported a synergistic interaction of D1/D5-receptor function and N-methyl-D-aspartate (NMDA)-receptors for L-LTP. Furthermore, we have found the requirement of the atypical protein kinase C isoform, protein kinase MĪ¶ (PKMĪ¶) for conventional electrically induced L-LTP, in which PKMĪ¶ has been identified as a LTP-specific plasticity-related protein (PRP) in apical CA1-dendrites. Here, we investigated whether the dopaminergic pathway activates PKMĪ¶. We found that application of dopamine (DA) evokes a protein synthesis-dependent LTP that requires synergistic NMDA-receptor activation and protein synthesis in apical CA1-dendrites. We identified PKMĪ¶ as a DA-induced PRP, which exerted its action at activated synaptic inputs by processes of synaptic tagging
Persistent Increases of PKMĪ¶ in Sensorimotor Cortex Maintain Procedural Long-Term Memory Storage
Summary: Procedural motor learning and memory are accompanied by changes in synaptic plasticity, neural dynamics, and synaptogenesis. Missing is information on the spatiotemporal dynamics of the molecular machinery maintaining these changes. Here we examine whether persistent increases in PKMĪ¶, an atypical protein kinase C (PKC) isoform, store long-term memory for a reaching task in rat sensorimotor cortex that could reveal the sites of procedural memory storage. Specifically, perturbing PKMĪ¶ synthesis (via antisense oligodeoxynucleotides) and blocking atypical PKC activity (via zeta inhibitory peptide [ZIP]) in S1/M1 disrupts and erases long-term motor memory maintenance, indicating atypical PKCs and specifically PKMĪ¶ store consolidated long-term procedural memories. Immunostaining reveals that PKMĪ¶ increases in S1/M1 layers II/III and V as performance improved to an asymptote. After storage for 1Ā month without reinforcement, the increase in M1 layer V persists without decrement. Thus, the persistent increases in PKMĪ¶ that store long-term procedural memory are localized to the descending output layer of the primary motor cortex. : Neuroscience; Behavioral Neuroscience; Molecular Neuroscience Subject Areas: Neuroscience, Behavioral Neuroscience, Molecular Neuroscienc
Memory enhancement and formation by atypical PKM activity in Drosophila
articles The study of PKC in memory formation has a long history The roles of PKC in hippocampal models of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) have been studied extensivel
Increased PKMĪ¶ activity impedes lateral movement of GluA2-containing AMPA receptors
Abstract Protein kinase M zeta (PKMĪ¶), a constitutively active, atypical protein kinase C isoform, maintains a high level of expression in the brain after the induction of learning and long-term potentiation (LTP). Further, its overexpression enhances long-term memory and LTP. Thus, multiple lines of evidence suggest a significant role for persistently elevated PKMĪ¶ levels in long-term memory. The molecular mechanisms of how synaptic properties are regulated by the increase in PKMĪ¶, however, are still largely unknown. The Ī±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) mediates most of the fast glutamatergic synaptic transmission in the brain and is known to be critical for the expression of synaptic plasticity and memory. Importance of AMPAR trafficking has been implicated in PKMĪ¶-mediated cellular processes, but the detailed mechanisms, particularly in terms of regulation of AMPAR lateral movement, are not well understood. In the current study, using a single-molecule live imaging technique, we report that the overexpression of PKMĪ¶ in hippocampal neurons immobilized GluA2-containing AMPARs, highlighting a potential novel mechanism by which PKMĪ¶ may regulate memory and synaptic plasticity