MicroRNA-22 Gates Long-Term Heterosynaptic Plasticity in Aplysia through Presynaptic Regulation of CPEB and Downstream Targets

Fiumara, Ferdinando; Rajasethupathy, Priyamvada; Antonov, Igor; Kosmidis, Stylianos; Sossin, Wayne S.; Kandel, Eric R.

doi:10.1016/j.celrep.2015.05.034

Cited by 63 publications

(48 citation statements)

References 34 publications

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“…For example, the propensity of CPEB to transition from a soluble to aggregated conformation is intrinsically dependent on protein expression level. As mentioned earlier, transcription of ApCPEB is upregulated in response to 5-HT, leading to elevated protein expression and subsequent aggregation by a variety of structural mechanisms (Raveendra et al 2013;Fiumara et al 2015). Moreover, CPEB expression is regulated by microRNAs (miRNAs).…”

Section: Aggregation Of Functional Prions Is Regulatedmentioning

confidence: 99%

“…Moreover, CPEB expression is regulated by microRNAs (miRNAs). In particular, a neuron-specific miRNA, miRNA-22, inhibits ApCPEB mRNA through multiple 3 0 UTR binding sites and is downregulated by serotonin (Fiumara et al 2015). Inhibition of miR-22 simulates the effect of serotonin treatment, further increasing CPEB levels and enhancing long-term facilitation.…”

Section: Aggregation Of Functional Prions Is Regulatedmentioning

confidence: 99%

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Functional Prions in the Brain

Rayman

Kandel

2016

Cold Spring Harb Perspect Biol

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Prions are proteins that can adopt self-perpetuating conformations and are traditionally regarded as etiological agents of infectious neurodegenerative diseases in humans, such as Creutzfeldt-Jakob disease, kuru, and transmissible encephalopathies. More recently, a growing consensus has emerged that prion-like, self-templating mechanisms also underlie a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, and Huntington's disease. Perhaps most surprising, not all prion-like aggregates are associated with pathological changes. There are now several examples of prion-like proteins in mammals that serve positive biological functions in their aggregated state. In this review, we discuss functional prions in the nervous system, with particular emphasis on the cytoplasmic polyadenylation element-binding protein (CPEB) and the role of its prion-like aggregates in synaptic plasticity and memory. We also mention a more recent example of a functional prion-like protein in the brain, TIA-1, and its role during stress. These studies of functional prion-like proteins have provided a number of generalizable insights on how prion-based protein switches may operate to serve physiological functions in higher eukaryotes.

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Section: Aggregation Of Functional Prions Is Regulatedmentioning

confidence: 99%

Section: Aggregation Of Functional Prions Is Regulatedmentioning

confidence: 99%

Functional Prions in the Brain

Rayman

Kandel

2016

Cold Spring Harb Perspect Biol

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“…Several putative mechanisms for maintaining PKMζ have been proposed, including positive feedback loops at the levels of PKMζ mRNA transcription (Chen et al, 2014; Hernandez et al, 2014; Ko et al, 2016), translation of the PKMζ message (Fiumara et al, 2015; Jalil, Sacktor, & Shouval, 2015; Westmark et al, 2010), and PKMζ protein stability (Sacktor, 2011). How these mechanisms become engaged during memory formation and thus sustain PKMζ during memory maintenance are fundamental questions for elucidating how memories are stored.…”

Section: Discussionmentioning

confidence: 99%

Persistent increased PKMζ in long-term and remote spatial memory

Hsieh

Tsokas

Serrano

et al. 2017

Neurobiology of Learning and Memory

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PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase’s action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1 day to 1 month after training. Therefore, if the mechanisms of PKMζ’s persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1 day to 1 month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase’s action during long-term and remote spatial memory maintenance.

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“…This raised the ques- tion: How does the heterosynaptic modulator 5-HT-which induces learning-related longterm plasticity of sensorimotor neuron synapses-determine the initial up-regulation, and the consequent conversion of CPEB into its aggregated state in the presynaptic sensory neurons? In search of a mechanism whereby 5-HT up-regulates the levels of ApCPEB in sensory neurons, Fiumara et al (2015) identified an Aplysia microRNA 22 (miR-22) that is expressed in sensory neurons. MiR-22 is down-regulated by 5-HT and inhibition of miR-22 increases CPEB levels and enhances LTF, mimicking the effect of 5-HT-dependent up-regulation of CPEB.…”

Section: Microrna-22 Gates Long-term Heterosynaptic Plasticity In Aplmentioning

confidence: 99%