scholarly journals Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1705
Author(s):  
Ipsit Srivastava ◽  
Erika Vazquez-Juarez ◽  
Lukas Henning ◽  
Marta Gómez-Galán ◽  
Maria Lindskog
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Rat Model ◽  
Synaptic Function ◽  
Mao B ◽  
Gaba Inhibition ◽  
Sensitive Line ◽  
Gaba Synthesis ◽  
Depression Disorder

A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline.

Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression

2016 ◽  
Vol 29 (1) ◽  
pp. 54-58 ◽  
Author(s):  
Xi-Cong Liu ◽  
Sophie Erhardt ◽  
Michel Goiny ◽  
Göran Engberg ◽  
Aleksander A. Mathé
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
High Performance ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Genetic Animal Model ◽  
Animal Model Of Depression ◽  
Tryptophan Metabolites ◽  
Sensitive Line

ObjectiveThere is a growing interest in the role of kynurenine pathway and tryptophan metabolites in the pathophysiology of depression. In the present study, the metabolism of tryptophan along the kynurenine pathway was analysed in a rat model of depression.MethodsKynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were measured by high-performance liquid chromatography (HPLC) in prefrontal cortex (PFC) and frontal cortex (FC) in a rat model of depression, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats. In addition, KYNA was also measured in hippocampus, striatum and cerebellum.ResultsKYNA levels were reduced in the PFC of FSL rats compared with FRL rats, but did not differ with regard to the FC, hippocampus, striatum or cerebellum. 3-HK levels in PFC and FC, representing the activity of the microglial branch of the kynurenine pathway, did not differ between the FSL and FRL strains.ConclusionOur results suggest an imbalanced metabolism of the kynurenine pathway in the PFC of FSL rats.

scholarly journals Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease

2019 ◽  
Vol 20 (14) ◽  
pp. 3407 ◽  
Author(s):  
Paola Imbriani ◽  
Annalisa Tassone ◽  
Maria Meringolo ◽  
Giulia Ponterio ◽  
Graziella Madeo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Caspase 3 ◽  
Cysteine Proteases ◽  
Synaptic Function ◽  
Adult Brain ◽  
Striatal Slices

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

scholarly journals Intracellular Ca2+ Release and Synaptic Plasticity: A Tale of Many Stores

2018 ◽  
Vol 25 (3) ◽  
pp. 208-226 ◽  
Author(s):  
Zahid Padamsey ◽  
William J. Foster ◽  
Nigel J. Emptage
Keyword(s):  
Endoplasmic Reticulum ◽  
Synaptic Plasticity ◽  
Synaptic Function ◽  
Intracellular Organelles ◽  
Short And Long Term ◽  
Central Synapses ◽  
Neural Signaling ◽  
Temporal Extent

Ca2+ is an essential trigger for most forms of synaptic plasticity. Ca2+ signaling occurs not only by Ca2+ entry via plasma membrane channels but also via Ca2+ signals generated by intracellular organelles. These organelles, by dynamically regulating the spatial and temporal extent of Ca2+ elevations within neurons, play a pivotal role in determining the downstream consequences of neural signaling on synaptic function. Here, we review the role of three major intracellular stores: the endoplasmic reticulum, mitochondria, and acidic Ca2+ stores, such as lysosomes, in neuronal Ca2+ signaling and plasticity. We provide a comprehensive account of how Ca2+ release from these stores regulates short- and long-term plasticity at the pre- and postsynaptic terminals of central synapses.

Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 21
Author(s):  
Rosario Sanchez-Pernaute ◽  
Anna-Liisa Brownell ◽  
◽  
Keyword(s):  
Positron Emission Tomography ◽  
Synaptic Plasticity ◽  
Metabotropic Glutamate Receptor ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Emission Tomography ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Mglu5 Receptors

Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinson’s disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series ofin vivostudies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinson’s disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia cortico–subcortical loops.

MicroRNA Profiling in Postmortem Brain and Plasma Exosomes: Biomarker Perspective of Suicidality

2017 ◽  
Vol 41 (S1) ◽  
pp. S49-S50
Author(s):  
Y. Dwivedi
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Microrna Expression ◽  
Postmortem Brain ◽  
Mrna Targets ◽  
Competing Interest ◽  
And Coping ◽  
Chromosomal Loci ◽  
Normal Controls

IntroductionSuicide is a leading cause of death. Although research on the biological aspects of suicide is accumulating, there is no testable biomarker to assess suicidality. miRNAs, small non-coding RNAs, have been implicated in synaptic plasticity, genetic susceptibility to stress and coping to stress response. Because of the presence of microRNAs in circulating body fluids, miRNAs can not only be used as regulators of disease pathologies but also in prognosis and treatment response.ObjectivesWhether miRNAs can be used as biomarker for suicidality.AimsTo examine miRNA expression in brain of suicide victims and in plasma exosomes of suicidal individuals.MethodsmicroRNA expression was studied in prefrontal cortex of depressed suicide subjects and healthy normal controls. Role of microRNAs in synaptic plasticity was studied by examining total and synaptonerosomes. microRNA expression was also studied in plasma exosomes of depressed non-suicide and depressed suicide subjects and healthy normal controls.ResultsWe found a global down–regulation of miRNAs in depressed subjects (21 miRNAs significantly down-regulated). Many of them were synaptically enriched and encoded at nearby chromosomal loci, shared motifs within the 5’-seeds, and shared putative mRNA targets. In addition, we found a dramatic reorganization of microRNAs in a coordinated and cohesive fashion in depressed subjects. We also detected changes in miRNAs in plasma exosomes of depressed suicide subjects that corresponded to microRNA changes in prefrontal cortex.ConclusionOur study provides critical evidence that microRNAs play a major role in suicide pathophysiology and that these microRNAs can be reliably used as peripheral biomarker.Disclosure of interestThe author declares that he has no competing interest.

scholarly journals Role of MicroRNA in Governing Synaptic Plasticity

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yuqin Ye ◽  
Hongyu Xu ◽  
Xinhong Su ◽  
Xiaosheng He
Keyword(s):  
Synaptic Plasticity ◽  
Neurological Disorders ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Synaptic Function ◽  
The Novel ◽  
Individual Mirnas ◽  
Underlying Mechanisms ◽  
And Function

Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases.

scholarly journals Emerging Concepts and Functions of Autophagy as a Regulator of Synaptic Components and Plasticity

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 34 ◽  
Author(s):  
YongTian Liang
Keyword(s):  
Synaptic Plasticity ◽  
Protein Interactions ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Protein Protein Interactions ◽  
Neuronal Function ◽  
And Function ◽  
Cellular Components ◽  
Neuronal Autophagy

Protein homeostasis (proteostasis) is crucial to the maintenance of neuronal integrity and function. As the contact sites between neurons, synapses rely heavily on precisely regulated protein-protein interactions to support synaptic transmission and plasticity processes. Autophagy is an effective degradative pathway that can digest cellular components and maintain cellular proteostasis. Perturbations of autophagy have been implicated in aging and neurodegeneration due to a failure to remove damaged proteins and defective organelles. Recent evidence has demonstrated that autophagosome formation is prominent at synaptic terminals and neuronal autophagy is regulated in a compartment-specific fashion. Moreover, synaptic components including synaptic proteins and vesicles, postsynaptic receptors and synaptic mitochondria are known to be degraded by autophagy, thereby contributing to the remodeling of synapses. Indeed, emerging studies indicate that modulation of autophagy may be required for different forms of synaptic plasticity and memory formation. In this review, I will discuss our current understanding of the important role of neuronal/synaptic autophagy in maintaining neuronal function by degrading synaptic components and try to propose a conceptual framework of how the degradation of synaptic components via autophagy might impact synaptic function and contribute to synaptic plasticity.

scholarly journals Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Luye Qin ◽  
Jamal B. Williams ◽  
Tao Tan ◽  
Tiaotiao Liu ◽  
Qing Cao ◽  
...  
Keyword(s):  
Risk Factor ◽  
Prefrontal Cortex ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Treatment Strategies ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Brain Diseases ◽  
Risk Genes

AbstractASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases.

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