Abstract P762: Hippocampal Plasticity Deficits After Cerebellar Stroke

Cerebellar stroke-induced cognitive and affective symptoms (CCAS) have been observed in patients with infarcts localized to the posterior regions of the cerebellum. Our lab has developed a mouse model of cerebellar stroke in which mice with posterior infarcts display hippocampal-dependent memory deficits. Synaptic plasticity in the hippocampal area CA1 is essential for episodic memory consolidation. There is evidence of functional connectivity of cerebellum with contralateral hippocampus. Therefore, we hypothesize that changes in after cerebellar stroke are the result of synaptic plasticity impairments within the hippocampus. We used a photothrombotic model to induce stroke in the posterior cerebellar hemispheres. Seven days after stroke, we performed extracellular recordings of field excitatory postsynaptic potentials (fEPSP) within the CA1 region of acute brain slices. In shams, theta-burst stimulation (TBS) of Schaffer collateral inputs produced long-term potentiation (LTP). TBS failed to evoke an increase in fEPSP slope in contralateral hippocampus of mice at 7 days post-injury. These data provide strong evidence demonstrating that injury to the cerebellum can produce changes in synaptic function within the hippocampus. The lack of LTP impairment in ipsilateral hippocampus after cerebellar stroke suggests that the observed plasticity deficits are activity dependent. We also observed reduced NMDA receptor, Fos and Arc expression. Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors is required for LTP and memory formation. We tested whether enhancement of TrkB signaling with the agonist 7, 8 dihydroflavone (DHF) could improve hippocampal plasticity. We observed a full restoration of hippocampal LTP in slices from cerebellar stroke mice that were incubated with DHF (250 nM) prior to TBS. We provide strong evidence for hippocampal dysfunction following cerebellar stroke. Our data have implications for benefit of strategies to enhance neurotrophic signaling not only at the site of injury, but in non-injured regions as well.

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High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus

Scientific Reports ◽

10.1038/s41598-021-83008-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Raul Loera-Valencia ◽

Erika Vazquez-Juarez ◽

Alberto Muñoz ◽

Gorka Gerenu ◽

Marta Gómez-Galán ◽

...

Keyword(s):

Pyramidal Neurons ◽

Memory Function ◽

Long Term Potentiation ◽

Synaptic Function ◽

Cholesterol Homeostasis ◽

Stratum Radiatum ◽

Actin Binding ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Term Potentiation

AbstractAlterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.

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Noradrenergic Regulation of Synaptic Plasticity in the Hippocampal CA1 Region

Journal of Neurophysiology ◽

10.1152/jn.1997.77.6.3013 ◽

1997 ◽

Vol 77 (6) ◽

pp. 3013-3020 ◽

Cited By ~ 154

Author(s):

Hiroshi Katsuki ◽

Yukitoshi Izumi ◽

Charles F. Zorumski

Keyword(s):

Synaptic Plasticity ◽

Receptor Antagonist ◽

Hippocampal Slices ◽

Stimulus Frequency ◽

Long Term Potentiation ◽

Receptor Activation ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1

Katsuki, Hiroshi, Yukitoshi Izumi, and Charles F. Zorumski. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J. Neurophysiol. 77: 3013–3020, 1997. The effects of norepinephrine (NE) and related agents on long-lasting changes in synaptic efficacy induced by several patterns of afferent stimuli were investigated in the CA1 region of rat hippocampal slices. NE (10 μM) showed little effect on the induction of long-term potentiation (LTP) triggered by theta-burst-patterned stimulation, whereas it inhibited the induction of long-term depression (LTD) triggered by 900 pulses of 1-Hz stimulation. In nontreated slices, 900 pulses of stimuli induced LTD when applied at lower frequencies (1–3 Hz), and induced LTP when applied at a higher frequency (30 Hz). NE (10 μM) caused a shift of the frequency-response relationship in the direction preferring potentiation. The effect of NE was most prominent at a stimulus frequency of 10 Hz, which induced no changes in control slices but clearly induced LTP in the presence of NE. The facilitating effect of NE on the induction of LTP by 10-Hz stimulation was blocked by theβ-adrenergic receptor antagonist timolol (50 μM), but not by the α receptor antagonist phentolamine (50 μM), and was mimicked by the β-agonist isoproterenol (0.3 μM), but not by the α1 agonist phenylephrine (10 μM). The induction of LTD by 1-Hz stimulation was prevented by isoproterenol but not by phenylephrine, indicating that the activation of β-receptors is responsible for these effects of NE. NE (10 μM) also prevented the reversal of LTP (depotentiation) by 900 pulses of 1-Hz stimulation delivered 30 min after LTP induction. In contrast to effects on naive (nonpotentiated) synapses, the effect of NE on previously potentiated synapses was only partially mimicked by isoproterenol, but fully mimicked by coapplication of phenylephrine and isoproterenol. In addition, the effect of NE was attenuated either by phentolamine or by timolol, indicating that activation of both α1 and β-receptors is required. These results show that NE plays a modulatory role in the induction of hippocampal synaptic plasticity. Althoughβ-receptor activation is essential, α1 receptor activation is also necessary in determining effects on previously potentiated synapses.

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Age-Related Cognitive Impairment: Role of Reduced Synaptobrevin-2 Levels in Deficits of Memory and Synaptic Plasticity

The Journals of Gerontology Series A ◽

10.1093/gerona/glz013 ◽

2019 ◽

Vol 75 (9) ◽

pp. 1624-1632 ◽

Cited By ~ 3

Author(s):

Albert Orock ◽

Sreemathi Logan ◽

Ferenc Deak

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

Learning And Memory ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Receptor Protein ◽

Protein Levels ◽

Ca1 Region ◽

Age Related ◽

Term Potentiation

AbstractCognitive impairment in the aging population is quickly becoming a health care priority, for which currently no disease-modifying treatment is available. Multiple domains of cognition decline with age even in the absence of neurodegenerative diseases. The cellular and molecular changes leading to cognitive decline with age remain elusive. Synaptobrevin-2 (Syb2), the major vesicular SNAP receptor protein, highly expressed in the cerebral cortex and hippocampus, is essential for synaptic transmission. We have analyzed Syb2 protein levels in mice and found a decrease with age. To investigate the functional consequences of lower Syb2 expression, we have used adult Syb2 heterozygous mice (Syb2+/−) with reduced Syb2 levels. This allowed us to mimic the age-related decrease of Syb2 in the brain in order to selectively test its effects on learning and memory. Our results show that Syb2+/− animals have impaired learning and memory skills and they perform worse with age in the radial arm water maze assay. Syb2+/− hippocampal neurons have reduced synaptic plasticity with reduced release probability and impaired long-term potentiation in the CA1 region. Syb2+/− neurons also have lower vesicular release rates when compared to WT controls. These results indicate that reduced Syb2 expression with age is sufficient to cause cognitive impairment.

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Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0813-4 ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

Enrico Faldini ◽

Tariq Ahmed ◽

Luc Bueé ◽

David Blum ◽

Detlef Balschun

Keyword(s):

Synaptic Plasticity ◽

Transgenic Mice ◽

Mouse Models ◽

Long Term Potentiation ◽

High Frequency Stimulation ◽

Synaptic Loss ◽

Ca1 Region ◽

Term Potentiation ◽

Frequency Stimulation

AbstractMany mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

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Nicotine Enhances the Depressive Actions of Aβ1–40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo

Journal of Neurophysiology ◽

10.1152/jn.00996.2002 ◽

2003 ◽

Vol 89 (6) ◽

pp. 2917-2922 ◽

Cited By ~ 35

Author(s):

D. B. Freir ◽

C. E. Herron

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Α7 Nicotinic Acetylcholine Receptor ◽

High Affinity ◽

Ca1 Region ◽

Α7 Nachr ◽

Term Potentiation ◽

Significant Depression

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (Aβ) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. Aβ is known to bind with high affinity to the α7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide Aβ1–40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of Aβ12–28 (icv), which binds with high affinity to the α7-nAChR and the specific α7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Aβ12–28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the α7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Aβ12–28 for binding to α7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of Aβ1–40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol Aβ1–40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with Aβ1–40 1 h prior to LTP induction caused a further significant depression of LTP compared with Aβ1–40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Aβ1–40. This then suggests that nicotine may exacerbate the depressive actions of Aβ on synaptic plasticity in AD.

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Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00835.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 479-489 ◽

Cited By ~ 143

Author(s):

Hey-Kyoung Lee ◽

Kogo Takamiya ◽

Kaiwen He ◽

Lihua Song ◽

Richard L. Huganir

Keyword(s):

Synaptic Plasticity ◽

Critical Role ◽

Long Term Potentiation ◽

Phosphorylation Sites ◽

Ca1 Region ◽

Term Potentiation ◽

Ampa Receptor Subunit ◽

Glur1 Subunit ◽

Activity Dependent

Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites (“double phosphomutants”), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the “double phosphomutants,” our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.

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Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

10.21203/rs.3.rs-41613/v1 ◽

2020 ◽

Author(s):

Mason L. Yeh ◽

Jessica R Yasko ◽

Eric S. Levine ◽

Betty A. Eipper ◽

Richard Mains

Keyword(s):

Synaptic Plasticity ◽

Molecular Mechanisms ◽

Long Term Potentiation ◽

Surface Expression ◽

Synaptic Function ◽

Nucleotide Exchange ◽

Long Term Depression ◽

Term Potentiation ◽

Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

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In Vivo Roles for Matrix Metalloproteinase-9 in Mature Hippocampal Synaptic Physiology and Plasticity

Journal of Neurophysiology ◽

10.1152/jn.00202.2007 ◽

2007 ◽

Vol 98 (1) ◽

pp. 334-344 ◽

Cited By ~ 102

Author(s):

Ozlem Bozdagi ◽

Vanja Nagy ◽

Kimberly T. Kwei ◽

George W. Huntley

Keyword(s):

Synaptic Plasticity ◽

Proteolytic Activity ◽

Neutralizing Antibodies ◽

Long Term Potentiation ◽

Receptor Activation ◽

Synaptic Function ◽

Loss Of Function ◽

Adult Rats ◽

Area Ca1

Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have well-known, mostly deleterious roles in remodeling after injury or stroke, but their role in nonpathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here we address the role of MMP-9 in hippocampal synaptic plasticity using both gain- and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of long-term potentiation (LTP) at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating nonpathological synaptic function and plasticity in mature hippocampus.

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

Stroke ◽

10.1161/str.51.suppl_1.tp111 ◽

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.

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