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Non-genetic Modifiers of Synaptic Plasticity and Neurotransmission in the Central Nervous System (CNS) in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 23921

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Guest Editor
Cellular Neurobiology & Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick V94 T9PX, Ireland
Interests: nanotechnology; neurobiology; gut-brain interaction; stem cells; proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

 Besides genetic factors, non-genetic factors influence how our brain develops and functions, influencing behavior and mental wellbeing. Despite an increasing understanding of how genes and their encoded proteins contribute to synaptic formation, plasticity, and function in the Central Nervous System, the interplay of non-genetic factors with these synaptic components remains poorly understood. However, both, genetic susceptibility and non-genetic factors affecting synapses may contribute to most brain disorders through a combination of disease-related gene variants and specific non-genetic factors that act as risk factors. This special issue focuses on the influence of non-genetic factors as modifiers of synaptic plasticity and neurotransmission in health and disease.

Recent advances in Eco-Neurobiology mean that we are now at a stage where it is feasible to start investigating the ways in which non-genetic factors act upon synapses on a mechanistic level. These factors (defined as “everything except that which is genetic”) include, but are not limited, to microbiota affecting synapses via the gut-brain axis, nutritional components such as lipids and trace metals, sex differences affecting synapse composition and function, immune diseases/ (neuro)inflammation, stress, drugs, or physical activity.

To understand gene-environment interaction on a molecular and mechanistic level, in vitro studies, studies using animal models, “omics” approaches or combinations of these may investigate processes such as alterations in synaptic gene expression, the synaptic proteome, synaptic signaling pathways, and synaptic activity, up to behavior.

Understanding how non-genetic factors contribute to synaptic dysfunction may lead to research strategies to normalize function in individuals with synaptopathies.

Dr. Andreas Grabrucker
Guest Editor

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Keywords

  • Neuroinflammation
  • Stress, Nutrition
  • Microbiota
  • Environment
  • Lipids
  • Trace metals
  • synapses
  • synaptic transmission
  • drugs
  • physical activity
  • brain
  • gut-brain axis

Published Papers (8 papers)

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Editorial

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3 pages, 475 KiB  
Editorial
Non-Genetic Modifiers of Synaptic Plasticity and Neurotransmission in the Central Nervous System (CNS) in Health and Disease
by Andreas M. Grabrucker
Int. J. Mol. Sci. 2022, 23(20), 12135; https://doi.org/10.3390/ijms232012135 - 12 Oct 2022
Viewed by 1224
Abstract
This Special Edition intends to focus on the influence of non-genetic factors as modifiers of synaptic plasticity and neurotransmission in health and disease [...] Full article
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Research

Jump to: Editorial, Review

18 pages, 3282 KiB  
Article
Hypothalamic NPY-Y1R Interacts with Gonadal Hormones in Protecting Female Mice against Obesity and Neuroinflammation
by Alessandra Oberto, Ilaria Bertocchi, Angela Longo, Sara Bonzano, Silvia Paterlini, Clara Meda, Sara Della Torre, Paola Palanza, Adriana Maggi and Carola Eva
Int. J. Mol. Sci. 2022, 23(11), 6351; https://doi.org/10.3390/ijms23116351 - 6 Jun 2022
Cited by 7 | Viewed by 2554
Abstract
We previously demonstrated that Npy1rrfb mice, which carry the conditional inactivation of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with male mice showing metabolic, hormonal and behavioral effects and females being only marginally affected. Moreover, exposure of [...] Read more.
We previously demonstrated that Npy1rrfb mice, which carry the conditional inactivation of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with male mice showing metabolic, hormonal and behavioral effects and females being only marginally affected. Moreover, exposure of Npy1rrfb male mice to a high-fat diet (HFD) increased body weight growth, adipose tissue, blood glucose levels and caloric intake compared to Npy1r2lox male controls. We used conditional knockout Npy1rrfb and Npy1r2lox control mice to examine whether forebrain disruption of the Npy1r gene affects susceptibility to obesity and associated disorders of cycling and ovariectomized (ovx) female mice in a standard diet (SD) regimen or exposed to an HFD for 3 months. The conditional deletion of the Npy1r gene increased body weight and subcutaneous white adipose tissue weight in both SD- and HFD-fed ovx females but not in cycling females. Moreover, compared with ovx control females on the same diet regimen, Npy1rrfb females displayed increased microglia number and activation, increased expression of Neuropeptide Y (NPY)-immunoreactivity (IR) and decreased expression of proopiomelanocortin-IR in the hypothalamic arcuate nucleus (ARC). These results suggest that in the ARC NPY-Y1R reduces the susceptibility to obesity of female mice with low levels of gonadal hormones and that this effect may be mediated via NPY-Y1R ability to protect the brain against neuroinflammation. Full article
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30 pages, 4843 KiB  
Article
Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma
by Carolina Urrutia-Ruiz, Daniel Rombach, Silvia Cursano, Susanne Gerlach-Arbeiter, Michael Schoen, Juergen Bockmann, Maria Demestre and Tobias M. Boeckers
Int. J. Mol. Sci. 2022, 23(11), 6081; https://doi.org/10.3390/ijms23116081 - 29 May 2022
Cited by 11 | Viewed by 3065
Abstract
Autism spectrum disorders (ASDs) are characterized by repetitive behaviors and impairments of sociability and communication. About 1% of ASD cases are caused by mutations of SHANK3, a major scaffolding protein of the postsynaptic density. We studied the role of SHANK3 in plastic [...] Read more.
Autism spectrum disorders (ASDs) are characterized by repetitive behaviors and impairments of sociability and communication. About 1% of ASD cases are caused by mutations of SHANK3, a major scaffolding protein of the postsynaptic density. We studied the role of SHANK3 in plastic changes of excitatory synapses within the central nervous system by employing mild traumatic brain injury (mTBI) in WT and Shank3 knockout mice. In WT mice, mTBI triggered ipsi- and contralateral loss of hippocampal dendritic spines and excitatory synapses with a partial recovery over time. In contrast, no significant synaptic alterations were detected in Shank311−/− mice, which showed fewer dendritic spines and excitatory synapses at baseline. In line, mTBI induced the upregulation of synaptic plasticity-related proteins Arc and p-cofilin only in WT mice. Interestingly, microglia proliferation was observed in WT mice after mTBI but not in Shank311−/− mice. Finally, we detected TBI-induced increased fear memory at the behavioral level, whereas in Shank311−/− animals, the already-enhanced fear memory levels increased only slightly after mTBI. Our data show the lack of structural synaptic plasticity in Shank3 knockout mice that might explain at least in part the rigidity of behaviors, problems in adjusting to new situations and cognitive deficits seen in ASDs. Full article
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16 pages, 4617 KiB  
Article
Inhibition of Glutamate Release, but Not of Glutamine Recycling to Glutamate, Is Involved in Delaying the Onset of Initial Lithium-Pilocarpine-Induced Seizures in Young Rats by a Non-Convulsive MSO Dose
by Marek J. Pawlik, Blanca I. Aldana, Lautaro F. Belfiori-Carrasco, Marta Obara-Michlewska, Mariusz P. Popek, Anna Maria Czarnecka and Jan Albrecht
Int. J. Mol. Sci. 2021, 22(20), 11127; https://doi.org/10.3390/ijms222011127 - 15 Oct 2021
Cited by 3 | Viewed by 2245
Abstract
Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition [...] Read more.
Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition of conversion of Glu/Gln precursors to neurotransmitter Glu, and/or from b) altered synaptic Glu release. Pilo was administered 60 min prior to sacrifice, MSO at 75 mg/kg, i.p., 2.5 h earlier. [1,2-13C]acetate and [U-13C]glucose were i.p.-injected either together with Pilo (short period) or 15 min before sacrifice (long period). Their conversion to Glu and Gln in the hippocampus and entorhinal cortex was followed using [13C] gas chromatography-mass spectrometry. Release of in vitro loaded Glu surrogate, [3H]d-Asp from ex vivo brain slices was monitored in continuously collected superfusates. [3H]d-Asp uptake was tested in freshly isolated brain slices. At no time point nor brain region did MSO modify incorporation of [13C] to Glu or Gln in Pilo-treated rats. MSO pretreatment decreased by ~37% high potassium-induced [3H]d-Asp release, but did not affect [3H]d-Asp uptake. The results indicate that MSO at a non-convulsive dose delays the initial Pilo-induced seizures by interfering with synaptic Glu-release but not with neurotransmitter Glu recycling. Full article
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22 pages, 9620 KiB  
Article
Early Life Febrile Seizures Impair Hippocampal Synaptic Plasticity in Young Rats
by Tatyana Y. Postnikova, Alexandra V. Griflyuk, Dmitry V. Amakhin, Anna A. Kovalenko, Elena B. Soboleva, Olga E. Zubareva and Aleksey V. Zaitsev
Int. J. Mol. Sci. 2021, 22(15), 8218; https://doi.org/10.3390/ijms22158218 - 30 Jul 2021
Cited by 18 | Viewed by 2600
Abstract
Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the [...] Read more.
Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain. Full article
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17 pages, 2041 KiB  
Article
Expression Analysis of Zinc Transporters in Nervous Tissue Cells Reveals Neuronal and Synaptic Localization of ZIP4
by Chiara A. De Benedictis, Claudia Haffke, Simone Hagmeyer, Ann Katrin Sauer and Andreas M. Grabrucker
Int. J. Mol. Sci. 2021, 22(9), 4511; https://doi.org/10.3390/ijms22094511 - 26 Apr 2021
Cited by 18 | Viewed by 2809
Abstract
In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. [...] Read more.
In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly controlled. Zinc transporters are key regulators of (extra-) cellular zinc levels, and deregulation of zinc homeostasis and zinc transporters has been associated with neurodegenerative and neuropsychiatric disorders. However, to date, the presence of specific family members and their subcellular localization within brain cells have not been investigated in detail. Here, we analyzed the expression of all zinc transporters (ZnTs) and Irt-like proteins (ZIPs) in the rat brain. We further used primary rat neurons and rat astrocyte cell lines to differentiate between the expression found in neurons or astrocytes or both. We identified ZIP4 expressed in astrocytes but significantly more so in neurons, a finding that has not been reported previously. In neurons, ZIP4 is localized to synapses and found in a complex with major postsynaptic scaffold proteins of excitatory synapses. Synaptic ZIP4 reacts to short-term fluctuations in local zinc levels. We conclude that ZIP4 may have a so-far undescribed functional role at excitatory postsynapses. Full article
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14 pages, 2444 KiB  
Article
Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction
by Bartłomiej Pochwat, Helena Domin, Anna Rafało-Ulińska, Bernadeta Szewczyk and Gabriel Nowak
Int. J. Mol. Sci. 2020, 21(13), 4791; https://doi.org/10.3390/ijms21134791 - 6 Jul 2020
Cited by 5 | Viewed by 5545
Abstract
Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) [...] Read more.
Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study. Full article
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Review

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21 pages, 1384 KiB  
Review
Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders
by Ann Katrin Sauer, Simone Hagmeyer and Andreas M. Grabrucker
Int. J. Mol. Sci. 2022, 23(11), 6082; https://doi.org/10.3390/ijms23116082 - 29 May 2022
Cited by 10 | Viewed by 3040
Abstract
Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of [...] Read more.
Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex pathology emerges, with alterations in the gastrointestinal and immune system and synaptic signaling in the brain, as a major consequence of prenatal zinc deficiency. The features represent a critical link in a causal chain that leads to various neuronal dysfunctions and behavioral phenotypes observed in prenatal zinc deficient (PZD) mice and probably other mouse models for ASD. Given that the complete phenotype of PZD mice may be key to understanding how non-genetic factors can modify the clinical features and severity of autistic patients and explain the observed heterogeneity, here, we summarize published data on PZD mice. We critically review the emerging evidence that prenatal zinc deficiency is at the core of several environmental risk factors associated with ASD, being mechanistically linked to ASD-associated genetic factors. In addition, we highlight future directions and outstanding questions, including potential symptomatic, disease-modifying, and preventive treatment strategies. Full article
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