Proton receptors regulate synapse-specific reconsolidation in the amygdala

AbstractDuring retrieval, aversive memories become labile during a period known as the reconsolidation window. When an extinction procedure is performed within the reconsolidation window, the original aversive memory can be replaced by one that is less traumatic. Our recent studies revealed that acidosis via inhalation of carbon dioxide (CO2) during retrieval enhances memory lability. However, the effects of CO2 inhalation on the central nervous system can be extensive, and there is a lack of prior evidence suggesting that the effects of CO2 are selective to a reactivated memory. The specific effects of CO2 depend on acid-sensing ion channels (ASICs), proton receptors that are involved in synaptic transmission and plasticity in the amygdala. Our previous patch-clamping data suggests that CO2 inhalation during retrieval increases activities of neurons in the amygdala that involve in the memory trace. In addition, CO2 inhalation during retrieval increases exchanges from Ca2+-impermeable to Ca2+-permeable AMPA receptors. Thus, we hypothesize that CO2 selectively potentiates memory lability in mice when inhaled during retrieval of aversive memory. In addition, CO2 inhalation alters memory lability via synaptic plasticity at selectively targeted synapses. Alterations in spine morphology after CO2 and retrieval with a specific stimulus indicates that CO2 selectively enhances synaptic plasticity. Overall, our results suggest that inhaling CO2 during the retrieval event increases the lability of an aversive memory through a synapse-specific reconsolidation process.

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Transient acidosis while retrieving a fear-related memory enhances its lability

eLife ◽

10.7554/elife.22564 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Jianyang Du ◽

Margaret P Price ◽

Rebecca J Taugher ◽

Daniel Grigsby ◽

Jamison J Ash ◽

...

Keyword(s):

Ion Channels ◽

Synaptic Transmission ◽

Pavlovian Conditioning ◽

Ampa Receptors ◽

Memory Trace ◽

Aversive Event ◽

Synaptic Signaling ◽

Acid Sensing Ion Channels ◽

Labile State ◽

Conditioning Experiments

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.

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Activation of acid‐sensing ion channels by carbon dioxide regulates amygdala synaptic protein degradation in memory reconsolidation

Molecular Brain ◽

10.1186/s13041-021-00786-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Boren Lin ◽

Khaled Alganem ◽

Sinead M. O’Donovan ◽

Zhen Jin ◽

FarzanehSadat Naghavi ◽

...

Keyword(s):

Carbon Dioxide ◽

Ion Channels ◽

Protein Degradation ◽

Ampa Receptors ◽

Memory Retrieval ◽

Memory Trace ◽

Ubiquitin Proteasome System ◽

Calcium Dependent ◽

Acid Sensing Ion Channels ◽

Ubiquitin Proteasome

AbstractReconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO2) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO2 inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO2 inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO2-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO2 inhalation.

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Faculty Opinions recommendation of Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732664991.793544181 ◽

2018 ◽

Author(s):

Johannes Hell

Keyword(s):

Synaptic Plasticity ◽

Ampa Receptors ◽

Homeostatic Synaptic Plasticity ◽

Phosphatase Regulation

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The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Molecules ◽

10.3390/molecules26051372 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1372

Author(s):

Tengrui Shi ◽

Jianxi Song ◽

Guanying You ◽

Yujie Yang ◽

Qiong Liu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Synaptic Plasticity ◽

Mouse Model ◽

Mouse Models ◽

Knockout Mouse ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Knockout Mouse Model ◽

The Central Nervous System

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

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Monitoring and Modulating Inflammation-Associated Alterations in Synaptic Plasticity: Role of Brain Stimulation and the Blood–Brain Interface

Biomolecules ◽

10.3390/biom11030359 ◽

2021 ◽

Vol 11 (3) ◽

pp. 359

Author(s):

Maximilian Lenz ◽

Amelie Eichler ◽

Andreas Vlachos

Keyword(s):

Synaptic Plasticity ◽

Brain Stimulation ◽

Vascular Function ◽

Neuropsychiatric Symptoms ◽

Systemic Infection ◽

Brain Functions ◽

Blood Brain ◽

Brain Interface ◽

The Central Nervous System

Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence has demonstrated that inflammatory cytokines affect the ability of neurons to express plasticity. It has been well-established that inflammation-associated alterations in synaptic plasticity contribute to the development of neuropsychiatric symptoms. Nevertheless, diagnostic approaches and interventional strategies to restore inflammatory deficits in synaptic plasticity are limited. Here, we review recent findings on inflammation-associated alterations in synaptic plasticity and the potential role of the blood–brain interface, i.e., the blood–brain barrier, in modulating synaptic plasticity. Based on recent findings indicating that brain stimulation promotes plasticity and modulates vascular function, we argue that clinically employed non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, could be used for monitoring and modulating inflammation-induced alterations in synaptic plasticity.

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Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Molecular Psychiatry ◽

10.1038/s41380-021-01140-y ◽

2021 ◽

Author(s):

Ahmed Eltokhi ◽

Miguel A. Gonzalez-Lozano ◽

Lars-Lennart Oettl ◽

Andrey Rozov ◽

Claudia Pitzer ◽

...

Keyword(s):

Synaptic Plasticity ◽

Social Interaction ◽

Social Behavior ◽

Ampa Receptors ◽

Signal To Noise Ratio ◽

Signal Transmission ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

Strong Impact ◽

Odor Processing

AbstractMutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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