ZIP It: Neural Silencing Is an Additional Effect of the PKM-Zeta Inhibitor Zeta-Inhibitory Peptide

LeBlancq, Michelle J.; McKinney, Ty L.; Dickson, Clayton T.

doi:10.1523/jneurosci.4563-14.2016

Cited by 31 publications

(28 citation statements)

References 40 publications

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“…There is an ongoing debate over whether the effect of ZIP on memory is due to PKM inhibition or if it results from nonspecific mechanisms of action (Lisman, 2012(Lisman, , 2017. Actually, PKM knock-out mice can form ZIP-sensitive memories (Lee et al, 2013;Volk et al, 2013) and ZIP induces seizures and reduces spontaneous hippocampal LFPs in anesthetized rats when used at concentrations 10 or more times higher than in our experiments (LeBlancq et al, 2016). At high concentrations, ZIP can also inhibit CaMKII and PKC/ (Pastalkova et al, 2006;Jalil et al, 2015), which can control AMPAR function and transport and compensate for PKM in PKM knock-out mice, respectively (Ren et al, 2013;Tsokas et al, 2016).…”

Section: Zip Does Not Affect Spontaneous Oscillatory Activity or Basamentioning

confidence: 55%

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

et al. 2019

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Object recognition memory (ORM) confers the ability to discriminate the familiarity of previously encountered items. Reconsolidation is the process by which reactivated memories become labile and susceptible to modifications. The hippocampus is specifically engaged in reconsolidation to integrate new information into the original ORM through a mechanism involving activation of brain-derived neurotrophic factor (BDNF) signaling and induction of LTP. It is known that BDNF can control LTP maintenance through protein kinase M (PKM), an atypical protein kinase C isoform that is thought to sustain memory storage by modulating glutamatergic neurotransmission. However, the potential involvement of PKM in ORM reconsolidation has never been studied. Using a novel ORM task combined with pharmacological, biochemical, and electrophysiological tools, we found that hippocampal PKM is essential to update ORM through reconsolidation, but not to maintain the inactive recognition memory trace stored over time, in adult male Wistar rats. Our results also indicate that hippocampal PKM acts downstream of BDNF and controls AMPAR synaptic insertion to elicit reconsolidation and suggest that blocking PKM activity during this process deletes active ORM.

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Section: Zip Does Not Affect Spontaneous Oscillatory Activity or Basamentioning

confidence: 55%

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

et al. 2019

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“…Recent studies have shown that ZIP used for inhibiting PKMζ may also inhibit other atypical PKC isotypes such as PKCi/λ (29), and also that ZIP could alter neuronal and network activity in a way that might be independent of PKMζ (30,31). In addition, PKCi/λ can compensate PKMζ in certain conditions (29,32,33).…”

Section: Resultsmentioning

confidence: 99%

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Navakkode

Rothkegel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyRmediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.A lzheimer's disease (AD), the most frequent form of dementia, is an age-related neurodegenerative disorder clinically characterized by early declarative memory deficits, followed by deterioration of other cognitive functions (1). The memory loss in AD is characterized by extracellular accumulation of amyloid β protein (Aβ) in the hippocampus and cerebral cortex preceding neurodegeneration (2, 3). Increasing evidence suggests that soluble forms of Aβ interfere with hippocampal synaptic plasticity mechanisms known to mediate learning and memory processes, including long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission (4-8). In particular, the protein synthesis-dependent late phase of LTP (L-LTP) is impaired in the hippocampus of various AD transgenic mouse models and in Aβ-treated hippocampal slices (4, 9), whereas LTD is facilitated (10) or not altered (10-12). It has been reported recently that Aβ-induced inhibition of LTP is mediated by extrasynaptic NMDA receptor activity, which prevents phosphorylation of the transcription factor cAMP response element-binding protein (13,14).Synaptic plasticity can be governed by a previous activity of the same postsynaptic neuron or neural network, a phenomenon referred to as metaplasticity (15). Metaplasticity orchestrates multiple aspects of functional plasticity and thus promotes long-term memory storage (16). For instance, inducing metaplasticity by activating ryanodine (RYA) receptors (RyRs) with its agonist RYA in hippocampal CA3-CA1 synapses lowers the threshold of LTP, resulting in enhanced LTP induction and persistence (17,18). In addition, metaplasticity can influence processes of associative memory storage as in the case for synaptic tagging and capture (STC) (17). STC is defined as the associative interactions between two independent sets of synapses within the same neuronal network, in which a synaptic...

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“…A recent example is the effect of knocking-out another second messenger molecule, PKM-ζ, in LTP. This was claimed as a landmark finding (Takeuchi et al 2014), but subsequent work showed that the knock-out altered other molecular and cellular effects besides PKM-ζ (see LeBlancq et al 2016), and produced unintended compensatory changes, thus weakening the claimed link (see Frankland and Josselyn 2016).…”

Section: Examples Of Psychoneural Reduction-the Cellular Basis Of Memorymentioning

confidence: 99%

Psychoneural reduction: a perspective from neural circuits

Parker

2019

Biol Philos

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Psychoneural reduction has been debated extensively in the philosophy of neuroscience. In this article I will evaluate metascientific approaches that claim direct molecular and cellular explanations of cognitive functions. I will initially consider the issues involved in linking cellular properties to behaviour from the general perspective of neural circuits. These circuits that integrate the molecular and cellular components underlying cognition and behaviour, making consideration of circuit properties relevant to reductionist debates. I will then apply this general perspective to specific systems where psychoneural reduction has been claimed, namely hippocampal long-term potentiation and the Aplysia gill-withdrawal reflex.

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ZIP It: Neural Silencing Is an Additional Effect of the PKM-Zeta Inhibitor Zeta-Inhibitory Peptide

Cited by 31 publications

References 40 publications

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

Psychoneural reduction: a perspective from neural circuits

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