scholarly journals FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

2019 ◽  
Vol 28 (22) ◽  
pp. 3777-3791 ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Sheue-Houy Tyan ◽  
Yi-Chun Yen ◽  
Kenneth Lim ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Dependent Manner ◽  
Spine Density ◽  
Preferential Expression ◽  
Fused In Sarcoma ◽  
Endogenous Expression ◽  
Term Potentiation ◽  
The Central Nervous System

Abstract Pathological fused in sarcoma (FUS) inclusions are found in 10% of patients with frontotemporal dementia and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.

scholarly journals Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

2021 ◽  
Vol 14 (1) ◽  
pp. 61
Author(s):  
Ernesto Fedele ◽  
Roberta Ricciarelli
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Gold Rush ◽  
New Drugs ◽  
Dose Finding ◽  
Beneficial Effects ◽  
Cyclic Nucleotide Gated Channels ◽  
Term Potentiation ◽  
Cgmp Signaling ◽  
The Central Nervous System

Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers.

scholarly journals Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Wan Yun Ho ◽  
Ira Agrawal ◽  
Sheue-Houy Tyan ◽  
Emma Sanford ◽  
Wei-Tang Chang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Brain Connectivity ◽  
Expression Patterns ◽  
Long Term Potentiation ◽  
Protein Homeostasis ◽  
Spine Density ◽  
Nonsense Mediated Decay ◽  
Endogenous Expression ◽  
Mitochondrial Functions

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.

Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area

2007 ◽  
Vol 26 (3) ◽  
pp. 749-756 ◽  
Author(s):  
Federica Sarti ◽  
Stephanie L. Borgland ◽  
Viktor N. Kharazia ◽  
Antonello Bonci
Keyword(s):  
Ventral Tegmental Area ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Cocaine Exposure ◽  
Term Potentiation ◽  
Ventral Tegmental

Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain

2017 ◽  
Vol 23 (6) ◽  
pp. 587-604 ◽  
Author(s):  
Julien Gibon ◽  
Philip A. Barker
Keyword(s):  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Cellular Processes ◽  
Term Potentiation ◽  
Neurotrophin 3 ◽  
New Findings ◽  
The Central Nervous System ◽  
The Brain

Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.

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

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 405 ◽  
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.

Spinal cord representation of motor cortex plasticity reflects corticospinal tract LTP

2021 ◽  
Vol 118 (52) ◽  
pp. e2113192118
Author(s):  
Alzahraa Amer ◽  
Jianxun Xia ◽  
Michael Smith ◽  
John H. Martin
Keyword(s):  
Spinal Cord ◽  
Motor Cortex ◽  
Corticospinal Tract ◽  
Cervical Spinal Cord ◽  
Long Term Potentiation ◽  
Dependent Manner ◽  
Term Potentiation ◽  
Spinal Cord Segment ◽  
Spinal Interneuron ◽  
Activity Dependent

Although it is well known that activity-dependent motor cortex (MCX) plasticity produces long-term potentiation (LTP) of local cortical circuits, leading to enhanced muscle function, the effects on the corticospinal projection to spinal neurons has not yet been thoroughly studied. Here, we investigate a spinal locus for corticospinal tract (CST) plasticity in anesthetized rats using multichannel recording of motor-evoked, intraspinal local field potentials (LFPs) at the sixth cervical spinal cord segment. We produced LTP by intermittent theta burst electrical stimulation (iTBS) of the wrist area of MCX. Approximately 3 min of MCX iTBS potentiated the monosynaptic excitatory LFP recorded within the CST termination field in the dorsal horn and intermediate zone for at least 15 min after stimulation. Ventrolaterally, in the spinal cord gray matter, which is outside the CST termination field in rats, iTBS potentiated an oligosynaptic negative LFP that was localized to the wrist muscle motor pool. Spinal LTP remained robust, despite pharmacological blockade of iTBS-induced LTP within MCX using MK801, showing that activity-dependent spinal plasticity can be induced without concurrent MCX LTP. Pyramidal tract iTBS, which preferentially activates the CST, also produced significant spinal LTP, indicating the capacity for plasticity at the CST–spinal interneuron synapse. Our findings show CST monosynaptic LTP in spinal interneurons and demonstrate that spinal premotor circuits are capable of further modifying descending MCX control signals in an activity-dependent manner.

scholarly journals Modeling Resilience to Damage in Multiple Sclerosis: Plasticity Meets Connectivity

2019 ◽  
Vol 21 (1) ◽  
pp. 143 ◽  
Author(s):  
Mario Stampanoni Bassi ◽  
Ennio Iezzi ◽  
Luigi Pavone ◽  
Georgia Mandolesi ◽  
Alessandra Musella ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Synaptic Plasticity ◽  
Network Architecture ◽  
White Matter Lesions ◽  
Long Term Potentiation ◽  
Chronic Inflammatory Disease ◽  
Brain Network ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Efficient Information

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.

Neuronal calcium sensors and synaptic plasticity

2009 ◽  
Vol 37 (6) ◽  
pp. 1359-1363 ◽  
Author(s):  
Mascia Amici ◽  
Andrew Doherty ◽  
Jihoon Jo ◽  
David Jane ◽  
Kwangwook Cho ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Signalling Pathways ◽  
Calcium Sensor ◽  
Calcium Sensors ◽  
Term Potentiation ◽  
Neuronal Calcium Sensor Protein ◽  
The Central Nervous System ◽  
Sensor Proteins

Calcium entry plays a major role in the induction of several forms of synaptic plasticity in different areas of the central nervous system. The spatiotemporal aspects of these calcium signals can determine the type of synaptic plasticity induced, e.g. LTP (long-term potentiation) or LTD (long-term depression). A vast amount of research has been conducted to identify the molecular and cellular signalling pathways underlying LTP and LTD, but many components remain to be identified. Calcium sensor proteins are thought to play an essential role in regulating the initial part of synaptic plasticity signalling pathways. However, there is still a significant gap in knowledge, and it is only recently that evidence for the importance of members of the NCS (neuronal calcium sensor) protein family has started to emerge. The present minireview aims to bring together evidence supporting a role for NCS proteins in plasticity, focusing on emerging roles of NCS-1 and hippocalcin.

Klk8, a multifunctional protease in the brain and skin: analysis of knockout mice

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Shigetaka Yoshida
Keyword(s):  
Central Nervous System ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Synaptic Changes ◽  
Adhesive Molecules ◽  
High Level ◽  
Activity Dependent ◽  
The Brain

Abstract Klk8 is a tryptic serine protease with limited substrate specificity. Klk8 mRNA is expressed in many developing organs, whereas its expression is confined to limited regions, including the hippocampus, in adults. In the hippocampus, Klk8 is involved in activity-dependent synaptic changes such as long-term potentiation, which was found to be suppressed in Klk8 knockout (KO) mice. Oligodendrocytes only expressed Klk8 mRNA after injury to the central nervous system. The epidermis of the skin is one of the tissues that exhibits a high level of KLK8 expression. Klk8 might be involved in desquamation through the degradation of adhesive molecules that connect layers of the epidermis. Klk8 might thus be involved in tissue development and rearrangement.

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