Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

Weng, Feng Ju; Garcia, Rodrigo I.; Lutzu, Stefano; Alviña, Karina; Zhang, Yuxiang; Dushko, Margaret; Ku, Taeyun; Zemoura, Khaled; Rich, David; Garcia-Dominguez, Dario; Hung, Matthew; Yelhekar, Tushar D.; Sørensen, Andreas T.; Xu, Weifeng; Chung, Kwanghun; Castillo, Pablo E.; Lin, Yingxi

doi:10.1016/j.neuron.2018.01.026

Cited by 79 publications

(64 citation statements)

References 63 publications

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“…While the signals that result in NPAS4 induction have not been characterized, the downstream consequences of its expression are evident. NPAS4 functions to regulate neural circuit connectivity (Bloodgood et al, 2013;Hartzell et al, 2018;Spiegel et al, 2014;Weng et al, 2018), and Npas4 knockout mice exhibit severe cognitive deficits and seizures (Coutellier et al, 2012;Lin et al, 2008). Thus, understanding the type of activity that leads to NPAS4 expression will also illuminate what depolarizing signals are transformed by the genome into changes in circuit connectivity.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Genomic decoding of neuronal depolarization by stimulus-specific NPAS4 heterodimers

Brigidi

Hayes

Hartzell

et al. 2019

Preprint

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transport to the dendrites would result in inverted spatiotemporal dynamics from what we observed (Farris et al., 2014;Okuno et al., 2012).Summation of EPSPs during tetanic stimulation produces large NMDAR-mediated Ca signals and may, in principle, gate L-VGCCs localized to the apical dendrites or soma (Magee and Johnston, 1995;Marrion and Tavalin, 1998). To determine if one or both of these Ca sources are associated with synaptically-induced NPAS4, afferents in SR were stimulated in the presence of NMDAR or L-VGCC antagonists (CPP and Nim, respectively; Figure S1J).Blockade of NMDARs prevented NPAS4 induction in the dendrites and soma, whereas antagonism of L-VGCCs had no effect (Figure 1J). This result indicates that activation of NMDARs, but not L-VGCCs, accounts for both the dendritic and somatic NPAS4 protein induced by synaptic potentials. Thus, APs and EPSPs originating in SR engage distinct Ca sources to induce NPAS4 and result in NPAS4 expression patterns with unique spatiotemporal profiles along the somato-dendritic axis of the PN.NPAS4 protein has not been previously observed in the dendrites of PNs, thus we sought to determine if sensory experiences can induce dendritic NPAS4 in vivo. Mice (P21−28) were transferred from their home cage (HC) into an enriched environment (EE) for 5 minutes, and then returned to their HC (Figure 1K). At various time points after return to the HC (1−90 min), hippocampi were removed, fixed, sectioned and stained for NPAS4 and NeuN. In WT mice, NPAS4 protein was detected in SR 3−5 minutes after exposure to EE, followed by an increase in immunofluorescence in SP (Figure 1L, M), recapitulating our observations in acute slices.Deletion of Npas4 in excitatory neurons (Npas4 f/f :: Emx1 Cre ) eliminated the experiencedependent NPAS4 induction in SR and SP (Figure 1N), whereas Npas4 knockout in inhibitory neurons (Npas4 f/f :: GAD2 Cre ) had no impact (Figure 1O), indicating that dendritic and somatic NPAS4 protein is produced in PNs. Moreover, analysis of other hippocampal subregions revealed dendritically localized NPAS4 in CA3 PNs (Figure S2A−D) suggesting this expression profile may be a general feature of PNs. In dentate granule cells, NPAS4 protein was detected within minutes of return to the HC (Figure S2E−H) but was not clearly localized to dendrites, possibly due to their compact morphologies. Thus, immediately after novel sensory experiences NPAS4 protein is observed in the dendrites of PNs in vivo, reflecting increases in local synaptic transmission.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Genomic decoding of neuronal depolarization by stimulus-specific NPAS4 heterodimers

Brigidi

Hayes

Hartzell

et al. 2019

Preprint

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“…Recent data suggest that memory precision defects can be generated by deregulation of genes involved in hippocampus Dentate Gyrus-CA3 connections, in particular Dentate Gyrus Mossy Fibers (MF)-CA3 synapse (18,(34)(35)(36)(37)(38). A During contextual fear memory consolidation, the strength of mossy fiber connections is selectively increased between dentate gyrus engram cells and CA3 engram cells (i.e.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A up-regulation specifically impairs a presynaptic form of long-term potentiation

Lepagnol-Bestel

Haziza

Viard

et al. 2019

Preprint

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Chromosome 21 DYRK1A kinase has long been associated with a variety of psychiatric diseases including Down Syndrome. We previously showed that Dyrk1A interacts with SWI/SNF (SWItch/Sucrose Non-Fermentable) nucleosome remodeling complex inducing expression changes of genes encoding key neuronal proteins. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated the YAC 152F7 (570 kb) encoding six chromosome 21 genes including DYRK1A.We found that DYRK1A Interacts with the key chromatin remodelers EP300 and CREBBP.Moreover, we observed changes in the transcriptional levels of genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2, Rab3A.This result prompted us to investigate the two main forms of long-term potentiation (LTP) required for learning and memory: the (N-methyl d-aspartate) receptor-dependent postsynaptic form versus the glutamate release-dependent presynaptic form. Interestingly, extracellular electrophysiological recordings in hippocampal slices of the YAC mouse line revealed that only the presynaptic forms of plasticity were impacted, leaving the post-synaptic form of plasticity intact. To refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicate the gene Dyrk1A. Again, we found that this presynaptic form of LTP is also impaired in this mouse line. This result demonstrates that abnormal up-regulation of Dyrk1A alone is sufficient to inhibit specifically the presynaptic forms of LTP. Altogether, our results suggest that impairment of DYRK1A gene dosage may impact memory precision, and therefore reinforce our mechanistic understanding of the cognitive impairment detected in this mouse model.

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“…Overall, these genes may play a crucial role in the excitatory/inhibitory synapse balance of the neural circuity by the selective regulation of Npas4 on specific cell types. Moreover, activated Npas4 in the hippocampus and amygdala is engaged in fear memory and synaptic modulation . Recently, a transcriptome analysis of cortical neurons after application of lactate showed upregulation of Npas4 at the mRNA level .…”

Section: Lactate As a Signaling Moleculementioning

confidence: 99%

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction

Wan

Dong

et al. 2019

BioEssays

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l‐Lactate is emerging as a crucial regulatory nexus for energy metabolism in the brain and signaling transduction in synaptic plasticity, memory processes, and drug addiction instead of being merely a waste by‐product of anaerobic glycolysis. In this review, the role of lactate in various memory processes, synapse plasticity and drug addiction on the basis of recent studies is summarized and discussed. To this end, three main parts are presented: first, lactate as an energy substrate in energy metabolism of the brain is described; second, lactate as a novel signaling molecule in synaptic plasticity, neural circuits, memory, and drug addiction is described; and third, in light of the above descriptions, it is plausible to speculate that lactate is predominantly a signaling molecule in specific memory processes and partly acts as an energy substrate. The future perspective in lactate signaling involving microglia and associated precise signaling pathways in the brain is highlighted.

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Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

Cited by 79 publications

References 63 publications

WITHDRAWN: Genomic decoding of neuronal depolarization by stimulus-specific NPAS4 heterodimers

WITHDRAWN: Genomic decoding of neuronal depolarization by stimulus-specific NPAS4 heterodimers

DYRK1A up-regulation specifically impairs a presynaptic form of long-term potentiation

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction

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