Bidirectional Regulation of eEF2 Phosphorylation Controls Synaptic Plasticity by Decoding Neuronal Activity Patterns

McCamphill, Patrick K.; Farah, Carole A.; Anadolu, Mina N.; Hoque, Sanjida; Sossin, Wayne S.

doi:10.1523/jneurosci.2376-14.2015

Cited by 38 publications

(65 citation statements)

References 62 publications

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“…Intriguingly, training significantly decreased p-eIF2α in the auditory area MNM (Figure 4a, left panel), but not in the visual area IMM (Figure 4a, right panel). To examine whether a reduction in eIF2α phosphorylation is required for auditory imprinting we treated chickens before training with Sal003, an inhibitor of the eIF2α phosphatase complexes (McCamphill et al, 2015), which increases p-eIF2α levels (Figure 4b and Figure 4—figure supplement 1) and decreases translation (Figure 4—figure supplement 2). Interestingly, increasing p-eIF2α with Sal003 prevented auditory imprinting, but had no effect on visual imprinting (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

Translational control of auditory imprinting and structural plasticity by eIF2α

Batista

Johnson

Dominguez

et al. 2016

eLife

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The formation of imprinted memories during a critical period is crucial for vital behaviors, including filial attachment. Yet, little is known about the underlying molecular mechanisms. Using a combination of behavior, pharmacology, in vivo surface sensing of translation (SUnSET) and DiOlistic labeling we found that, translational control by the eukaryotic translation initiation factor 2 alpha (eIF2α) bidirectionally regulates auditory but not visual imprinting and related changes in structural plasticity in chickens. Increasing phosphorylation of eIF2α (p-eIF2α) reduces translation rates and spine plasticity, and selectively impairs auditory imprinting. By contrast, inhibition of an eIF2α kinase or blocking the translational program controlled by p-eIF2α enhances auditory imprinting. Importantly, these manipulations are able to reopen the critical period. Thus, we have identified a translational control mechanism that selectively underlies auditory imprinting. Restoring translational control of eIF2α holds the promise to rejuvenate adult brain plasticity and restore learning and memory in a variety of cognitive disorders.DOI: http://dx.doi.org/10.7554/eLife.17197.001

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Section: Resultsmentioning

confidence: 99%

Translational control of auditory imprinting and structural plasticity by eIF2α

Batista

Johnson

Dominguez

et al. 2016

eLife

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“…To determine if increased levels of KIBRA are sufficient to maintain memories by stabilizing PKMs, we induced m-ITF in neurons expressing KIBRA. KIBRA did not, however, increase m-ITF at 2h after induction, a time in which m-ITF has decayed to baseline (McCamphill et al, 2015;Sutton et al, 2002) (Fig. 4B).…”

Section: Kibra Overexpression Is Not Sufficient To Prolong Itfmentioning

confidence: 85%

“…There are different forms of ITF based on the stimulation, but massed ITF (m-ITF) is of particular interest as it requires cleavage of PKC Apl III to PKM Apl III since: (i) it is blocked by DN PKM Apl III, (ii) it is blocked by a DN form of the protease that cleaves PKCs to PKMs, DN classical calpain, and (iii) stimulation that induces m-ITF causes cleavage of a PKC Apl III FRET construct in the motor neuron (Bougie et al, 2012;Farah et al, 2017). Despite the requirement for a PKM, this form of facilitation is transient (McCamphill et al, 2015;Sutton et al, 2002). One hypothesis is that PKMs are made but not stabilized in the absence of KIBRA and thus transcriptional upregulation of KIBRA could be important for the prolongation of PKM activity and increases in synaptic strength.…”

Section: Kibra Overexpression Is Not Sufficient To Prolong Itfmentioning

confidence: 99%

Isoform specificity of PKMs during long-term facilitation in Aplysia is mediated through stabilization by KIBRA

Ferguson

Cai

et al. 2019

Preprint

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Persistent activity of protein kinase M (PKM), the truncated form of protein kinase C (PKC), can maintain long-term changes in synaptic strength in many systems including the hermaphrodite marine mollusk, Aplysia californica. Moreover, different types of long-term facilitation (LTF) in cultured Aplysia sensorimotor synapses rely on the activities of different PKM isoforms in the presynaptic sensory neuron and postsynaptic motor neuron. When the atypical PKM isoform was required, the kidney and brain expressed adaptor protein (KIBRA) was also required. Here, we explore how this isoform specificity is established. We find that PKM overexpression in the motor neuron, but not the sensory neuron, is sufficient to increase synaptic strength and that this activity is not isoform specific. KIBRA is not the rate-limiting step in facilitation since overexpression of KIBRA is neither sufficient to increase synaptic strength, nor to prolong a form of PKM-dependent intermediate synaptic facilitation. However, the isoform specificity of dominant negative (DN)-PKMs to erase LTF is correlated with isoform specific competition for stabilization by KIBRA. We identify a new conserved region of KIBRA. Different splice isoforms in this region stabilize different PKMs based on the isoform-specific sequence of an alpha-helix 'handle' in the PKMs. Thus, specific stabilization of distinct PKMs by different isoforms of KIBRA can explain the isoform specificity of PKMs during LTF in Aplysia. 3 Significance StatementLong lasting changes in synaptic plasticity associated with memory formation are maintained by persistent protein kinases. We have previously shown in the Aplysia sensorimotor model that distinct isoforms of persistently active protein kinase Cs (PKMs) maintain distinct forms of long-lasting synaptic changes, even when both forms are expressed in the same motor neuron. Here, we show that, while the effects of overexpression of PKMs in not isoform specific, isoform specificity is defined by a 'handle' helix in PKMs that confers stabilization by distinct splice forms in a previously undefined domain of the adaptor protein KIBRA. Thus, we define new regions in both KIBRA and PKMs that define the isoform specificity for maintaining synaptic strength in distinct facilitation paradigms.

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“…The data obtained using cortical cultures derived from eEF2K-KO mice led to the notion that the eEF2K pathway accounts for the increase in protein synthesis following dopamine D1 receptor activation. eEF2K has been identified as a biochemical sensor that is tuned to the pattern of neuronal stimulation (Heise et al, 2014, McCamphill et al, 2015, Sutton et al, 2007. Perturbation of intracellular calcium concentration by NMDA and neuronal activity produces eEF2K/eEF2-dependent changes of dendritic proteome (Ehlers, 2003, Lazarevic et al, 2011, Perez-Otano and Ehlers, 2005, Turrigiano, 2008, Turrigiano and Nelson, 2004, Virmani et al, 2006.…”

Section: Nmdar-d1 Partnership Induces Translational Changes Via Erk Amentioning

confidence: 99%

“…Given this complex regulation of its function, it is tempting to speculate that eEF2K works as a signaling hub, linking synaptic activity to protein synthesis. Conversely, eEF2 dephosphorylation occurs by spaced 5-HT activity and the PKA stimulation (McCamphill et al, 2015). eEF2K activity can be regulated by the type of neurotransmission in which eEF2K acts as a biochemical sensor to discriminate between evoked action potential and spontaneous miniature synaptic transmission (Sutton 2007).…”

Section: Nmdar-d1 Partnership Induces Translational Changes Via Erk Amentioning

confidence: 99%

MEK/mTOR-dependent D1 dopamine receptor activation induces local protein synthesis via eEF2 dephosphorylation in neurons

David

Barrera

Koltun

et al. 2018

Preprint

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One-sentence summary: D1 receptor activation increases protein synthesis in dendrites by inactivating eEF2K in an ERK2/mTOR-dependent manner. AbstractNeuromodulators in general, and dopamine in particular, define brain and neuronal states in different ways including regulation of global and local mRNA translation. Yet, the signaling pathways underlying the effects of dopamine on mRNA translation are not clear. Here, using genetic, pharmacologic, biochemical, and imaging methods, we tested the hypothesis that dopamine regulates phosphorylation of the eukaryotic elongation factor 2 (eEF2). We found that activation of dopamine receptor D1 but not D2 leads to rapid dephosphorylation of eEF2 at Thr 56 in cortical primary neuronal culture and in vivo in a time-dependent manner. Additionally, NMDA receptor, mTOR, and ERK pathways are upstream to the D1 receptor-dependent eEF2 dephosphorylation and essential for it. Furthermore, D1 receptor activation resulted in a major reduction in dendritic eEF2 phosphorylation levels together with a correlative increase in local mRNA translation. These results reveal the role of eEF2 in dopamine regulation of local mRNA translation in neurons.

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Bidirectional Regulation of eEF2 Phosphorylation Controls Synaptic Plasticity by Decoding Neuronal Activity Patterns

Cited by 38 publications

References 62 publications

Translational control of auditory imprinting and structural plasticity by eIF2α

Translational control of auditory imprinting and structural plasticity by eIF2α

Isoform specificity of PKMs during long-term facilitation in Aplysia is mediated through stabilization by KIBRA

MEK/mTOR-dependent D1 dopamine receptor activation induces local protein synthesis via eEF2 dephosphorylation in neurons

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