scholarly journals A schizophrenia risk gene, NRGN, bidirectionally modulates synaptic plasticity via regulating the neuronal phosphoproteome

2018 ◽  
Author(s):  
Hongik Hwang ◽  
Matthew J. Szucs ◽  
Lei J. Ding ◽  
Andrew Allen ◽  
Henny Haensgen ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Contextual Fear Conditioning ◽  
Significant Shift ◽  
Cellular Functions ◽  
Current Decay ◽  
Risk Gene ◽  
Postsynaptic Density Proteins ◽  
Neuronal Proteins ◽  
Schizophrenic Patients

AbstractNRGN is a schizophrenia risk gene identified in recent genetic studies, encoding a small neuronal protein, neurogranin (Ng). Individuals carrying a risk variant of NRGN showed decreased hippocampal activation during contextual fear conditioning. Furthermore, the expression of Ng was reduced in the post-mortem brains of schizophrenic patients. Using the mouse model, we found that the translation of Ng in hippocampus is rapidly increased in response to novel context exposure, and this up-regulation is required for encoding contextual memory. The extent and degree of the effect that altered Ng expression has on neuronal cellular functions are largely unknown. Here, we found that Ng bidirectionally regulates synaptic plasticity in the hippocampus. Elevated Ng levels facilitated long-term potentiation (LTP), whereas decreased Ng levels impaired LTP. Quantitative phosphoproteomic analysis revealed that decreasing Ng caused a significant shift in the phosphorylation status of postsynaptic density proteins, highlighting clusters of schizophrenia- and autism-related genes. In particular, decreasing Ng led to the hypo-phosphorylation of NMDAR subunit Grin2A at newly identified sites, resulting in accelerated decay of NMDAR-mediated channel currents. blocking protein phosphatase PP2B activity rescued the accelerated synaptic NMDAR current decay and the impairment of LTP caused by decreased Ng levels, suggesting that enhanced synaptic PP2B activity led to the deficits. Taken together, our work suggests that altered Ng levels under pathological conditions affect the phosphorylation status of neuronal proteins by tuning PP2B activity and thus the induction of synaptic plasticity, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.

Abstract TP111: TRPM2 is a Therapeutic Target for Reversal of Stroke-Induced Dementia-Like Symptoms

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
James E Orfila ◽  
Robert M Dietz ◽  
Andra Dingman ◽  
Christian M Schroeder ◽  
Nidia Quillinan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Fear Conditioning ◽  
Memory Function ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Contextual Fear Conditioning ◽  
Trpm2 Channel ◽  
Trpm2 Channels

Introduction: Cognitive impairments and memory loss are common after stroke, with an emerging awareness of a high risk of conversion to post-stroke dementia. It is increasingly clear that in addition to neuronal injury following cerebral ischemia, impaired functional networks contribute to long-term functional deficits. Synaptic plasticity (long term potentiation; LTP) is the leading cellular model of learning and memory. Thus, we utilize electrophysiological recordings of hippocampal LTP as an indicator of network health following ischemia in combination with neurobehavioral assessments of memory function. TRPM2 channels are oxidative stress sensitive ion channels that have been implicated in ischemic injury. Hypothesis: Inhibition of TRPM2 channels reverse stroke-induced cognitive deficits. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared 30 days after recovery from transient MCAO (45 min) in adult (6-8 week) mice. A behavioral fear conditioning paradigm was used to evaluate contextual memory 30 days after MCAO. Slices or mice were treated with our newly developed peptide inhibitor of TRPM2, termed tatM2NX. Results: Recordings obtained in brain slices 30 days after MCAO exhibited near complete loss of LTP; 161±9%, n=6 in sham compared to 115±4%, n=7 30 days after MCAO in the ipsilateral hippocampus. Similar deficit in LTP observed in the contralateral hippocampus. Remarkably, iv injection of 20 mg/kg tatM2NX on day 29 after MCAO reversed MCAO-induced loss of LTP when recorded on day 30, recovering to 175±9% (n=3). Memory function, measured using contextual fear conditioning, was consistent with our LTP findings. MCAO decreased freezing behavior, indicating lack of memory (62±5% in sham mice (n=5) and 24±3% in MCAO mice, n=4). This was reversed in MCAO mice given tatM2NX (20 mg/kg iv injection 24 hr before testing) on day 29 post MCAO, increasing freezing to 73±12% (n=3). Conclusion: These data indicate that our new TRPM2 channel inhibitor, tatM2NX, restores synaptic plasticity and memory function after experimental stroke. Therefore, inhibition of TRPM2 channels at chronic timepoints following ischemia may represent a novel strategy to improve functional recovery following stroke.

scholarly journals Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Nicholas E. Clifton ◽  
Darren Cameron ◽  
Simon Trent ◽  
Lucy H. Sykes ◽  
Kerrie L. Thomas ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Novelty Detection ◽  
Postsynaptic Density ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Contextual Fear ◽  
Postsynaptic Density Proteins ◽  
Genes Encoding

Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of shortHomer1isoforms,Homer1aandAnia-3, is thought to be related to processes of learning and memory. However, the precise regulation ofHomer1aandAnia-3with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and longHomer1expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats.Homer1aandAnia-3, but not longHomer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity.

scholarly journals Corticosteroid Regulation of Synaptic Plasticity in the Hippocampus

2010 ◽  
Vol 10 ◽  
pp. 462-469 ◽  
Author(s):  
Nicola Maggio ◽  
Menahem Segal
Keyword(s):  
Synaptic Plasticity ◽  
Stress Level ◽  
Cognitive Functions ◽  
Molecular Mechanisms ◽  
High Stress ◽  
Long Term Potentiation ◽  
Cellular Functions ◽  
Effects Of Stress

Stress, via release of steroid hormones, has been shown to affect several cellular functions in the brain, including synaptic receptors and ion channels. As such, corticosteroids were reported to modulate plasticity, expressed as long-term changes in reactivity to afferent stimulation. The classical view of the effects of stress on synaptic plasticity and cognitive functions assumes an inverted U-shape curve, such that a low stress level facilitates and a high stress level (i.e., corticosterone levels) impairs cognitive functions. This universal view has been challenged recently in a series of studies that show that stress and corticosterone have immediate and opposite effects on the ability to express long-term potentiation (LTP) in the dorsal and ventral sectors of the hippocampus. This differential role of stress may be related to the different functions associated with these sectors of the hippocampus. Herein, we review the known effects of stress hormones on cellular functions and outline the role of molecular mechanisms in stress-related global functions of the hippocampus.

Cyclooxygenase-2 Regulates Prostaglandin E2 Signaling in Hippocampal Long-Term Synaptic Plasticity

2002 ◽  
Vol 87 (6) ◽  
pp. 2851-2857 ◽  
Author(s):  
Chu Chen ◽  
Jeffery C. Magee ◽  
Nicolas G. Bazan
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Postsynaptic Membrane ◽  
Synaptic Activity ◽  
Perforant Path ◽  
Membrane Excitability ◽  
Cellular Functions ◽  
Cox 2 ◽  
Cox 1

The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca2+ influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE2 but not of PGD2 or PGF2α. Our results indicate that COX-2-generated PGE2regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.

c-Jun N-terminal kinases in memory and synaptic plasticity

2011 ◽  
Vol 22 (4) ◽  
Author(s):  
Tessi Sherrin ◽  
Thomas Blank ◽  
Cedomir Todorovic
Keyword(s):  
Synaptic Plasticity ◽  
Fear Conditioning ◽  
Long Term Potentiation ◽  
Contextual Fear Conditioning ◽  
Contextual Fear ◽  
Term Potentiation ◽  
Stress Signal ◽  
Mitogen Activated Protein ◽  
Jnk Isoforms ◽  
Future Work

AbstractThe c-Jun N-terminal kinases (JNK) belong to the subfamily of mitogen-activated protein kinases (MAPK). JNK is an important signaling enzyme that is involved in many facets of cellular regulation including gene expression, cell proliferation and programmed cell death. Activation of JNK isoforms (JNK1, 2, and 3) is regarded as a molecular switch in stress signal transduction. The activation of JNK pathways is also critical for pathological death associated with neurodegenerative diseases. Considering that a variety of stressors activate JNK, it is surprising that the role of hippocampal JNK in memory and synaptic plasticity has not yet been systematically investigated. Here we summarize the emerging evidence for the functions of hippocampal JNK in memory and synaptic plasticity, including our recent demon­stration that JNK isoforms play critical roles in regulation of contextual fear conditioning under stressful and baseline conditions. We postulate that sustained activation of the hippocampal JNK2 and JNK3 pathways is involved in the initial stress response that ultimately leads to deficits in memory and long-term potentiation, whereas transient JNK1 activation regulates baseline contextual fear conditioning. Results obtained within the framework of our recent findings will be used for future work, which will differentiate mechanisms underlying beneficial short-term JNK action from prolonged JNK activation that may lead to memory deficits and neurodegeneration.

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Yu-Xing Ge ◽  
Ying-Ying Lin ◽  
Qian-Qian Bi ◽  
Yu-Juan Chen
Keyword(s):  
Synaptic Plasticity ◽  
Temporal Lobe Epilepsy ◽  
Synaptic Vesicle ◽  
Long Term Potentiation ◽  
Synaptic Dysfunction ◽  
Over Expression ◽  
Term Potentiation ◽  
Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

scholarly journals In-Frame and Frameshift Mutations in Zebrafish presenilin 2 Affect Different Cellular Functions in Young Adult Brains

2021 ◽  
pp. 1-10
Author(s):  
Karissa Barthelson ◽  
Stephen Martin Pederson ◽  
Morgan Newman ◽  
Haowei Jiang ◽  
Michael Lardelli
Keyword(s):  
Cell Cycle ◽  
Young Adult ◽  
Oxidative Phosphorylation ◽  
Frameshift Mutation ◽  
Long Term Potentiation ◽  
Cellular Functions ◽  
Reading Frame ◽  
Term Potentiation ◽  
Presenilin 2

Background: Mutations in PRESENILIN 2 (PSEN2) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. Objective: To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques. Methods: A frameshift mutation (psen2N140fs) and a reading frame-preserving (in-frame) mutation (psen2T141 _ L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed. Results: The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. Conclusion: A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

scholarly journals Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning

Hippocampus ◽  
2013 ◽  
Vol 24 (2) ◽  
pp. 204-213 ◽  
Author(s):  
W. Bailey Glen ◽  
Bryant Horowitz ◽  
Gregory C. Carlson ◽  
Tyrone D. Cannon ◽  
Konrad Talbot ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Fear Conditioning ◽  
Contextual Fear Conditioning ◽  
Contextual Fear

Prenatal stress in rats attenuates hippocampal long-term potentiation and induces deficits in synaptic plasticity

2006 ◽  
Vol 16 ◽  
pp. S52
Author(s):  
S. Salomon ◽  
Y. Nachum-Biala ◽  
Y. Bogush ◽  
M. Lineal ◽  
H. Matzner ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Prenatal Stress ◽  
Long Term Potentiation ◽  
Term Potentiation
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