Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

Lisman, John; Cooper, Katherine M.; Sehgal, Megha; Silva, Alcino J.

doi:10.1038/s41593-018-0076-6

Cited by 294 publications

(244 citation statements)

References 71 publications

(75 reference statements)

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“…Besides our in vivo data -restoring cognitive performance in the Y-Maze -we also show that BDNF rescues the LTP impairment observed in IL-17 -/-and TCRδ-/-mice. LTP is the main form of synaptic plasticity reflecting the activity of synaptic information storage processes, and has been often used as the gold standard cellular correlate of learning and memory in the hippocampus (43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here we show that noninflammatory IL-17 derived from a previously unknown foetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory, while retaining long-term memory.

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Section: Discussionmentioning

confidence: 99%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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“…In addition to the balance of inhibition and excitation, a number of other functional properties might be expected to modulate the oPDT, the oADT, or both. Synaptic strength determines the threshold for downstream propagation of the synchronous discharge (Nicoll, 2017), intrinsic excitability modulates the responsiveness of downstream cells, which is governed by the relative expression and cellular localization of voltage-gated Na + , K + , and Ca 2+ channels (Graef and Godwin, 2010;Lisman et al, 2018;Meadows et al, 2016), and the regulation of the extracellular space by glia (Devinsky et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability

Klorig

Alberto

Smith

et al. 2019

Preprint

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Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PD) that are nearly indistinguishable from spontaneously-occurring interictal spikes. By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced population discharge threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations. Significance StatementAbnormal excitability is associated with a number of neurological disorders, including epilepsy. Excitability can be measured in single cells in vitro, but it is difficult to extrapolate from these values to the functional impact on the associated network. Epileptiform population discharges are network-wide events that represent a distinct transition from normal to abnormal functional modes. We developed a new method that uses light intensity-response curves to precisely determine the threshold for this transition as a surrogate measure of network excitability.

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“…How does CREB activation by phosphorylation and CBP association confer neuroprotection remains unclear. Moreover, reports that this mode of CREB activation confers neuronal hyper excitability (Dong et al 2006;Soriano et al 2006;Yiu et al 2014;Lisman et al 2018) and cause neurodegeneration (Lopez de Armentia et al 2007;Valor et al 2010;Benito et al 2011) suggest that indiscriminative hyperactivation of CREB is unlikely to be productive and a neuroprotective approach in excitotoxicity. A number of recent studies have shown that in some important cases the non-canonical pathway is at play, involving CREB stabilization on the DNA by CRTC.…”

Section: Discussionmentioning

confidence: 99%

Non-Canonical Activation of CREB Mediates Neuroprotection in aC. elegansModel of Excitotoxic Necrosis

Chowdhury

Becker

et al. 2018

Preprint

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Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu-Receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP Response Element Binding-protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation-triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB Binding Protein (CBP). However, given CREB’s ubiquitous cross-tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely-tailored, differential neuroprotective responses in excitotoxicity. A non-canonical, alternative cascade for activation of CREB-mediated transcription involves the CREB co-factor cAMP-regulated transcriptional co-activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we use a C. elegans model of neurodegeneration by excitotoxic necrosis. We demonstrate that CREB’s neuroprotective effect is conserved, and seems most effective in neurons with moderate Glu exposure. We find that factors mediating canonical CREB activation are not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinges on CRTC. CREB-mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity-specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity.

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Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

Cited by 294 publications

References 71 publications

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability

Non-Canonical Activation of CREB Mediates Neuroprotection in aC. elegansModel of Excitotoxic Necrosis

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