The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF and AMPA and NMDA receptor-mediated long-term potentiation.

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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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The Anti-inflammatory Cytokine, Interleukin (IL)-10, Blocks the Inhibitory Effect of IL-1β on Long Term Potentiation

Journal of Biological Chemistry ◽

10.1074/jbc.m108757200 ◽

2001 ◽

Vol 276 (49) ◽

pp. 45564-45572 ◽

Cited By ~ 88

Author(s):

Áine Kelly ◽

Aileen Lynch ◽

Emily Vereker ◽

Yvonne Nolan ◽

Patrice Queenan ◽

...

Keyword(s):

Inflammatory Cytokine ◽

Long Term Potentiation ◽

Inhibitory Effect ◽

Term Potentiation ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

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Excavatolide-B Enhances Contextual Memory Retrieval via Repressing the Delayed Rectifier Potassium Current in the Hippocampus

Marine Drugs ◽

10.3390/md16110405 ◽

2018 ◽

Vol 16 (11) ◽

pp. 405 ◽

Cited By ~ 2

Author(s):

Irene Huang ◽

Yu-Luan Hsu ◽

Chien-Chang Chen ◽

Mei-Fang Chen ◽

Zhi-Hong Wen ◽

...

Keyword(s):

Memory Retrieval ◽

Potassium Current ◽

Memory Function ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Absence Epilepsy ◽

Delayed Rectifier ◽

Contextual Memory ◽

Term Potentiation ◽

Delayed Rectifier Potassium Current

Memory retrieval dysfunction is a symptom of schizophrenia, autism spectrum disorder (ASD), and absence epilepsy (AE), as well as an early sign of Alzheimer’s disease. To date, few drugs have been reported to enhance memory retrieval. Here, we found that a coral-derived natural product, excavatolide-B (Exc-B), enhances contextual memory retrieval in both wild-type and Cav3.2−/− mice via repressing the delayed rectifier potassium current, thus lowering the threshold for action potential initiation and enhancing induction of long-term potentiation (LTP). The human CACNA1H gene encodes a T-type calcium channel (Cav3.2), and its mutation is associated with schizophrenia, ASD, and AE, which are all characterized by abnormal memory function. Our previous publication demonstrated that Cav3.2−/− mice exhibit impaired contextual-associated memory retrieval, whilst their retrieval of spatial memory and auditory cued memory remain intact. The effect of Exc-B on enhancing the retrieval of context-associated memory provides a hope for novel drug development.

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Enhancement of neuroplasticity by drug therapy

Oxford Textbook of Neurorehabilitation ◽

10.1093/med/9780198824954.003.0017 ◽

2020 ◽

pp. 221-236

Author(s):

Ulf Ziemann

Keyword(s):

Basic Research ◽

Long Term Potentiation ◽

Basic Mechanism ◽

Human Studies ◽

Dependent Plasticity ◽

Open Questions ◽

Term Potentiation ◽

Specific Practice ◽

The Impact ◽

Activity Dependent

This chapter reviews effects of central nervous system (CNS) active drugs specifically on activity-dependent plasticity and learning. The rationale for choosing this focus is the existing evidence that CNS active drugs have an impact on rehabilitation success after stroke to a relevant extent only if coupled with task-specific practice. This chapter reviews pharmacological modulation of stimulation-induced long-term potentiation (LTP) in animal and human studies because synaptic plasticity in the form of LTP is a basic mechanism of learning and memory processes. Next, the chapter reviews the evidence of CNS active drugs on learning in animal and human studies. In the third part, the impact of CNS active drugs on neurorehabilitation of stroke patients is surveyed and the translational cascade from basic research to clinical studies is described. Finally, limitations of the current studies, open questions, and future directions are discussed. This chapter demonstrates significant impact of neuropharmacology on activity-dependent plasticity and learning.

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Early low-level developmental arsenic exposure impacts mouse hippocampal synaptic function

10.1101/2021.04.15.440033 ◽

2021 ◽

Author(s):

Karl F Foley ◽

Daniel Barnett ◽

Deborah A Cory-Slechta ◽

Houhui Xia

Keyword(s):

Synaptic Transmission ◽

Hippocampal Slices ◽

Arsenic Exposure ◽

Long Term Potentiation ◽

Epidemiological Studies ◽

Synaptic Function ◽

Learning Deficits ◽

Term Potentiation ◽

The Impact

Background: Arsenic is a well-established carcinogen known to increase all-cause mortality, but its effects on the central nervous system are less well understood. Recent epidemiological studies suggest that early life exposure to arsenic is associated with learning deficits and behavioral changes, and increased arsenic exposure continues to affect an estimated 200 million individuals worldwide. Previous studies on arsenic exposure and synaptic function have demonstrated a decrease in synaptic transmission and long-term potentiation in adult rodents, but have relied on in vitro or extended exposure in adulthood. Therefore, little is known about the effect of arsenic exposure in development. Objective: Here, we studied the effects of gestational and early developmental arsenic exposure in juvenile mice. Specifically, our objective was to investigate the impact of arsenic exposure on synaptic transmission and plasticity in the hippocampus. Methods: C57BL/6 females were exposed to arsenic (0, 50ppb, 36ppm) in their drinking water two weeks prior to mating and continued to be exposed to arsenic throughout gestation and after parturition. We then performed field recordings in acute hippocampal slices from the juvenile offspring prior to weaning (P17-P23). In this paradigm, the juvenile mice are only exposed to arsenic in utero and via the mothers milk. Results: High (36ppm) and relatively low (50ppb) arsenic exposure both lead to decreased basal synaptic transmission in the hippocampus of juvenile mice. There was a mild decrease in paired-pulse facilitation in juvenile mice exposed to high, but not low, arsenic, suggesting the alterations in synaptic transmission are primarily post-synaptic. Finally, high developmental arsenic exposure led to a significant increase in long-term potentiation. Discussion: These results suggest that indirect, ecologically-relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

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Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse

10.1101/253054 ◽

2018 ◽

Author(s):

Sooyun Kim ◽

Yoonsub Kim ◽

Suk-Ho Lee ◽

Won-Kyung Ho

Keyword(s):

Granule Cells ◽

Memory Function ◽

Brain Slices ◽

Long Term Potentiation ◽

Perforant Path ◽

Term Potentiation ◽

Dendritic Spikes ◽

Voltage Attenuation ◽

Synaptic Responses

AbstractLong-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na + ‐spike generation during PP-GC input. Inhibition of Na+ ‐spikes impairs LTP suggesting that LTP at PP-GC synapse requires local Na + ‐spikes. Thus, dendritic spikes are essential for LTP induction at PP-GC synapse and may constitute a key cellular mechanism for memory formation in the dentate gyrus.

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Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity

10.1101/2020.08.05.237420 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alexander Popov ◽

Alexey Brazhe ◽

Pavel Denisov ◽

Oksana Sutyagina ◽

Natalia Lazareva ◽

...

Keyword(s):

Volume Fraction ◽

Long Term Potentiation ◽

Two Photon Microscopy ◽

Two Photon ◽

Term Potentiation ◽

Hippocampal Ca1 ◽

Age Dependent ◽

And Function ◽

The Impact

Little is known about age-dependent changes in structure and function of astrocytes and of the impact of these into the cognitive decline in the senescent brain. The prevalent view on age-dependent increase in reactive astrogliosis and astrocytic hypertrophy requires scrutiny and detailed analysis. Using two-photon microscopy in conjunction with 3D reconstruction, Sholl and volume fraction analysis we demonstrate a significant reduction in the number and the length of astrocytic processes, in astrocytic territorial domains and in astrocyte-to-astrocyte coupling in the aged brain. Probing physiology of astrocytes with patch-clamp and Ca2+ imaging revealed deficits in K+ and glutamate clearance, and spatiotemporal reorganization of Ca2+ events in old astrocytes. These changes paralleled impaired synaptic long-term potentiation (LTP) in hippocampal CA1 in old mice. Our findings may explain astroglial mechanisms of age-dependent decline in learning and memory.

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Long-Term Moderate Exercise Rescues Age-Related Decline in Hippocampal Neuronal Complexity and Memory

Gerontology ◽

10.1159/000488589 ◽

2018 ◽

Vol 64 (6) ◽

pp. 551-561 ◽

Cited By ~ 15

Author(s):

Sheng-Feng Tsai ◽

Nai-Wen Ku ◽

Tzu-Feng Wang ◽

Yan-Hsiang Yang ◽

Yao-Hsiang Shih ◽

...

Keyword(s):

Learning And Memory ◽

Memory Function ◽

Long Term Potentiation ◽

Treadmill Running ◽

Moderate Intensity ◽

Middle Aged ◽

Ca1 Neurons ◽

Term Potentiation ◽

Old Mice

Background: Aging impairs hippocampal neuroplasticity and hippocampus-related learning and memory. In contrast, exercise training is known to improve hippocampal neuronal function. However, whether exercise is capable of restoring memory function in old animals is less clear. Objective: Here, we investigated the effects of exercise on the hippocampal neuroplasticity and memory functions during aging. Methods: Young (3 months), middle-aged (9–12 months), and old (18 months) mice underwent moderate-intensity treadmill running training for 6 weeks, and their hippocampus-related learning and memory, and the plasticity of their CA1 neurons was evaluated. Results: The memory performance (Morris water maze and novel object recognition tests), and dendritic complexity (branch and length) and spine density of their hippocampal CA1 neurons decreased as their age increased. The induction and maintenance of high-frequency stimulation-induced long-term potentiation in the CA1 area and the expressions of neuroplasticity-related proteins were not affected by age. Treadmill running increased CA1 neuron long-term potentiation and dendritic complexity in all three age groups, and it restored the learning and memory ability in middle-aged and old mice. Furthermore, treadmill running upregulated the hippocampal expressions of brain-derived neurotrophic factor and monocarboxylate transporter-4 in middle-aged mice, glutamine synthetase in old mice, and full-length TrkB in middle-aged and old mice. Conclusion: The hippocampus-related memory function declines from middle age, but long-term moderate-intensity running effectively increased hippocampal neuroplasticity and memory in mice of different ages, even when the memory impairment had progressed to an advanced stage. Thus, long-term, moderate intensity exercise training might be a way of delaying and treating aging-related memory decline.

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Simvastatin Impairs Hippocampal Synaptic Plasticity and Cognitive Function in Mice

10.21203/rs.3.rs-76680/v2 ◽

2021 ◽

Author(s):

Yujun Guo ◽

Guichang Zou ◽

Keke Qi ◽

Jin Jin ◽

Lei Yao ◽

...

Keyword(s):

Synaptic Plasticity ◽

Memory Function ◽

Long Term Potentiation ◽

Drug Discontinuation ◽

Cholesterol Levels ◽

Hippocampal Synaptic Plasticity ◽

Term Potentiation ◽

The Central Nervous System

Abstract Lipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive

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