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Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process

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 November 2020) | Viewed by 36969

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Giuseppina Martella

E-Mail Website
Guest Editor
Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia, University of Rome Tor Vergata, 00179 Rome, Italy
Interests: pathophysiology; movement disorders; motor memory; motor dysfunction; synaptic plasticity; brain circuitry; basal ganglia; striatum (putamen); medium spiny neurons; mitochondria; neurologic and phychiatric disorders; protein synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions”. (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/mechanisms_synaptic_plasticity)

Synaptic plasticity is a complex and crucial neuronal mechanism linked to principal memory and motor functions. During the developmental period into old age, the neural frame is subject to structural and functional modifications in response to external stimuli. This essential skill of neuronal cells underpins the ability to learn of mammalian organisms (Glanzman et al., 2010).

Synaptic plasticity phenomena include microscopic changes such as spine pruning and macroscopic changes such as cortical remapping in response to injury (Citri and Malenka 2008; Hofer et al., 2009). The increase of neurological and neuropsychiatric disorders in the current century—although this increase did not occur among the aging population—has resulted in an improved urgency to understand the aberrant processes connected to these diseases (Martella et al., 2016; 2018; Bonsi et al 2018).

In the last decades, it has been highlighted that de novo protein synthesis, (mRNA transcription mRNA and protein degradation, histone acetylation, DNA methylation, and miRNA regulation), as well as a new set of signaling molecules (endogenously generated cannabinoids, peptides, Neurotrophins, protein kinases, and ubiquitin-proteasome system), has been implicated in synaptic transmission and plasticity (McAllister et al ., 1999; Wilson & Nicoll 2001; Barki-Harrington et al., 2009; Belelovsky et al., 2009; Gal-Ben-Ari et al., 2012; Giese and Mizuno, 2013; Graff and Tsai, 2013; Jarome and Helmstetter, 2013; Saab and Mansuy, 2014).

The aim of this Special Issue is to collect original papers, reviews, case reports, and other forms of scientific communication that could increase the interest of scientists in synaptic plasticity phenomena.

Dr. Giuseppina Martella
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • synaptic plasticity
  • synaptic mechanism
  • synaptic response
  • neural network
  • neurological and neuropsychiatric disorders
  • molecular pathway
  • neuronal circuitry
  • dynamic changes in synapses
  • neuron function re-arraignments
  • motor and memory learning

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Editorial

Jump to: Research, Review

3 pages, 192 KiB  
Editorial
Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process
by Giuseppina Martella
Int. J. Mol. Sci. 2023, 24(16), 12685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612685 - 11 Aug 2023
Viewed by 596
Abstract
Due to the success of the first Special Issue on synaptic plasticity, I endeavored to promote a new Special Issue with an emphasis on dynamic changes in neuronal functions and physiological and pathological processes [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)

Research

Jump to: Editorial, Review

29 pages, 3864 KiB  
Article
miRNA-132/212 Deficiency Disrupts Selective Corticosterone Modulation of Dorsal vs. Ventral Hippocampal Metaplasticity
by Shima Kouhnavardi, Maureen Cabatic, M. Carmen Mañas-Padilla, Marife-Astrid Malabanan, Tarik Smani, Ana Cicvaric, Edison Alejandro Muñoz Aranzalez, Xaver Koenig, Ernst Urban, Gert Lubec, Estela Castilla-Ortega and Francisco J. Monje
Int. J. Mol. Sci. 2023, 24(11), 9565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119565 - 31 May 2023
Viewed by 1375
Abstract
Cortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as [...] Read more.
Cortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as its dysregulation is associated with debilitating conditions such as Alzheimer’s Disease, chronic stress, anxiety and depression. Among other brain regions, cortisol importantly influences the function of the hippocampus, a structure central for memory and emotional information processing. The mechanisms fine-tuning the different synaptic responses of the hippocampus to steroid hormone signaling remain, however, poorly understood. Using ex vivo electrophysiology and wild type (WT) and miR-132/miR-212 microRNAs knockout (miRNA-132/212−/−) mice, we examined the effects of corticosterone (the rodent’s equivalent to cortisol in humans) on the synaptic properties of the dorsal and ventral hippocampus. In WT mice, corticosterone predominantly inhibited metaplasticity in the dorsal WT hippocampi, whereas it significantly dysregulated both synaptic transmission and metaplasticity at dorsal and ventral regions of miR–132/212−/− hippocampi. Western blotting further revealed significantly augmented levels of endogenous CREB and a significant CREB reduction in response to corticosterone only in miR–132/212−/− hippocampi. Sirt1 levels were also endogenously enhanced in the miR–132/212−/− hippocampi but unaltered by corticosterone, whereas the levels of phospo-MSK1 were only reduced by corticosterone in WT, not in miR–132/212−/− hippocampi. In behavioral studies using the elevated plus maze, miRNA-132/212−/− mice further showed reduced anxiety-like behavior. These observations propose miRNA-132/212 as potential region-selective regulators of the effects of steroid hormones on hippocampal functions, thus likely fine-tuning hippocampus-dependent memory and emotional processing. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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16 pages, 2724 KiB  
Article
Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether
by Roberta De Rosa, Serena Valastro, Clara Cambria, Isabella Barbiero, Carolina Puricelli, Marco Tramarin, Silvia Randi, Massimiliano Bianchi, Flavia Antonucci and Charlotte Kilstrup-Nielsen
Int. J. Mol. Sci. 2023, 24(1), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010068 - 21 Dec 2022
Cited by 3 | Viewed by 1844
Abstract
CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on [...] Read more.
CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on neuronal inhibition has been poorly investigated. We explored the potential role of CDKL5 in the inhibitory compartment in Cdkl5-KO male mice and primary hippocampal neurons and found that CDKL5 interacts with gephyrin and collybistin, two crucial organisers of the inhibitory postsynaptic sites. Through molecular and electrophysiological approaches, we demonstrated that CDKL5 loss causes a reduced number of gephyrin puncta and surface exposed γ2 subunit-containing GABAA receptors, impacting the frequency of miniature inhibitory postsynaptic currents, which we ascribe to a postsynaptic function of CDKL5. In line with previous data showing that CDKL5 loss impacts microtubule (MT) dynamics, we showed that treatment with pregnenolone-methyl-ether (PME), which promotes MT dynamics, rescues the above defects. The impact of CDKL5 deficiency on inhibitory neurotransmission might explain the presence of drug-resistant epilepsy and cognitive defects in CDD patients. Moreover, our results may pave the way for drug-based therapies that could bypass the need for CDKL5 and provide effective therapeutic strategies for CDD patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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8 pages, 569 KiB  
Communication
Pattern of Mitochondrial Respiration in Peripheral Blood Cells of Patients with Parkinson’s Disease
by Tommaso Schirinzi, Illari Salvatori, Henri Zenuni, Piergiorgio Grillo, Cristiana Valle, Giuseppina Martella, Nicola Biagio Mercuri and Alberto Ferri
Int. J. Mol. Sci. 2022, 23(18), 10863; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810863 - 17 Sep 2022
Cited by 8 | Viewed by 1827
Abstract
Mitochondria are central in the pathogenesis of Parkinson’s disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims [...] Read more.
Mitochondria are central in the pathogenesis of Parkinson’s disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims to shape the pattern of mitochondrial respiration in the blood leukocytes of PD patients in relation to both clinical features and the profile of cerebrospinal fluid (CSF) biomarkers of neurodegeneration. Mitochondrial respirometry on the peripheral blood mononucleate cells (PBMCs) of 16 PD patients and 14 controls was conducted using Seahorse Bioscience technology. Bioenergetic parameters were correlated either with standard clinical scores for motor and non-motor disturbances or with CSF levels of α-synuclein, amyloid-β peptides, and tau proteins. In PD, PBMC mitochondrial basal respiration was normal; maximal and spare respiratory capacities were both increased; and ATP production was higher, although not significantly. Maximal and spare respiratory capacity was directly correlated with disease duration, MDS-UPDRS part III and Hoehn and Yahr motor scores; spare respiratory capacity was correlated with the CSF amyloid-β-42 to amyloid-β-42/40 ratio. We provided preliminary evidence showing that mitochondrial respiratory activity increases in the PBMCs of PD patients, probably following the compensatory adaptations to disease progression, in contrast to the bases of the neuropathological substrate. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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12 pages, 6058 KiB  
Article
Comparison of Cerebellar Grey Matter Alterations in Bipolar and Cerebellar Patients: Evidence from Voxel-Based Analysis
by Michela Lupo, Giusy Olivito, Andrea Gragnani, Marco Saettoni, Libera Siciliano, Corinna Pancheri, Matteo Panfili, Marco Bozzali, Roberto Delle Chiaie and Maria Leggio
Int. J. Mol. Sci. 2021, 22(7), 3511; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073511 - 29 Mar 2021
Cited by 14 | Viewed by 2501
Abstract
The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, [...] Read more.
The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I−IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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15 pages, 2220 KiB  
Article
A2A Receptor Dysregulation in Dystonia DYT1 Knock-Out Mice
by Vincenza D’Angelo, Mauro Giorgi, Emanuela Paldino, Silvia Cardarelli, Francesca R. Fusco, Ilaria Saverioni, Roberto Sorge, Giuseppina Martella, Stefano Biagioni, Nicola B. Mercuri, Antonio Pisani and Giuseppe Sancesario
Int. J. Mol. Sci. 2021, 22(5), 2691; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052691 - 07 Mar 2021
Cited by 7 | Viewed by 1982
Abstract
We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/− knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. The co-localization of A2A was [...] Read more.
We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/− knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. The co-localization of A2A was studied in striatal cholinergic interneurons identified by anti-choline-acetyltransferase (ChAT) antibody. A2A mRNA and cyclic adenosine monophosphate (cAMP) contents were also assessed. In Tor1a+/+, Western blotting detected an A2A 45 kDa band, which was stronger in the striatum and the globus pallidus than in the entopeduncular nucleus. Moreover, in Tor1a+/+, immunofluorescence showed A2A roundish aggregates, 0.3–0.4 μm in diameter, denser in the neuropil of the striatum and the globus pallidus than in the entopeduncular nucleus. In Tor1a+/−, A2A Western blotting expression and immunofluorescence aggregates appeared either increased in the striatum and the globus pallidus, or reduced in the entopeduncular nucleus. Moreover, in Tor1a+/−, A2A aggregates appeared increased in number on ChAT positive interneurons compared to Tor1a+/+. Finally, in Tor1a+/−, an increased content of cAMP signal was detected in the striatum, while significant levels of A2A mRNA were neo-expressed in the globus pallidus. In Tor1a+/−, opposite changes of A2A receptors’ expression in the striatal-pallidal complex and the entopeduncular nucleus suggest that the pathophysiology of dystonia is critically dependent on a composite functional imbalance of the indirect over the direct pathway in basal ganglia. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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13 pages, 1766 KiB  
Article
Long-Term Shaping of Corticostriatal Synaptic Activity by Acute Fasting
by Federica Campanelli, Daniela Laricchiuta, Giuseppina Natale, Gioia Marino, Valeria Calabrese, Barbara Picconi, Laura Petrosini, Paolo Calabresi and Veronica Ghiglieri
Int. J. Mol. Sci. 2021, 22(4), 1916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041916 - 15 Feb 2021
Cited by 2 | Viewed by 2373
Abstract
Food restriction is a robust nongenic, nonsurgical and nonpharmacologic intervention known to improve health and extend lifespan in various species. Food is considered the most essential and frequently consumed natural reward, and current observations have demonstrated homeostatic responses and neuroadaptations to sustained intermittent [...] Read more.
Food restriction is a robust nongenic, nonsurgical and nonpharmacologic intervention known to improve health and extend lifespan in various species. Food is considered the most essential and frequently consumed natural reward, and current observations have demonstrated homeostatic responses and neuroadaptations to sustained intermittent or chronic deprivation. Results obtained to date indicate that food deprivation affects glutamatergic synapses, favoring the insertion of GluA2-lacking α-Ammino-3-idrossi-5-Metil-4-idrossazol-Propionic Acid receptors (AMPARs) in postsynaptic membranes. Despite an increasing number of studies pointing towards specific changes in response to dietary restrictions in brain regions, such as the nucleus accumbens and hippocampus, none have investigated the long-term effects of such practice in the dorsal striatum. This basal ganglia nucleus is involved in habit formation and in eating behavior, especially that based on dopaminergic control of motivation for food in both humans and animals. Here, we explored whether we could retrieve long-term signs of changes in AMPARs subunit composition in dorsal striatal neurons of mice acutely deprived for 12 hours/day for two consecutive days by analyzing glutamatergic neurotransmission and the principal forms of dopamine and glutamate-dependent synaptic plasticity. Overall, our data show that a moderate food deprivation in experimental animals is a salient event mirrored by a series of neuroadaptations and suggest that dietary restriction may be determinant in shaping striatal synaptic plasticity in the physiological state. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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29 pages, 3669 KiB  
Article
Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome
by Daniela Laricchiuta, Giuseppe Sciamanna, Juliette Gimenez, Andrea Termine, Carlo Fabrizio, Silvia Caioli, Francesca Balsamo, Anna Panuccio, Marco De Bardi, Luana Saba, Noemi Passarello, Debora Cutuli, Anna Mattioni, Cristina Zona, Valerio Orlando and Laura Petrosini
Int. J. Mol. Sci. 2021, 22(2), 810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020810 - 15 Jan 2021
Cited by 6 | Viewed by 3580
Abstract
Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated [...] Read more.
Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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12 pages, 1016 KiB  
Article
Interleukin-1β Alters Hebbian Synaptic Plasticity in Multiple Sclerosis
by Mario Stampanoni Bassi, Fabio Buttari, Carolina Gabri Nicoletti, Francesco Mori, Luana Gilio, Ilaria Simonelli, Nicla De Paolis, Girolama Alessandra Marfia, Roberto Furlan, Annamaria Finardi, Diego Centonze and Ennio Iezzi
Int. J. Mol. Sci. 2020, 21(19), 6982; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21196982 - 23 Sep 2020
Cited by 6 | Viewed by 2202
Abstract
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using [...] Read more.
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1β levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1β may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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19 pages, 4151 KiB  
Article
Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner
by Abhisarika Patnaik, Eleonora Spiombi, Angelisa Frasca, Nicoletta Landsberger, Marta Zagrebelsky and Martin Korte
Int. J. Mol. Sci. 2020, 21(9), 3079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093079 - 27 Apr 2020
Cited by 17 | Viewed by 3278
Abstract
The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is [...] Read more.
The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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13 pages, 1166 KiB  
Article
Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function
by Giuseppe Di Giovanni, Laura Clara Grandi, Ernesto Fedele, Gergely Orban, Agnese Salvadè, Wei Song, Eleonora Cuboni, Alessandro Stefani, Alain Kaelin-Lang and Salvatore Galati
Int. J. Mol. Sci. 2020, 21(8), 2734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082734 - 15 Apr 2020
Cited by 7 | Viewed by 2489
Abstract
The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we [...] Read more.
The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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Review

Jump to: Editorial, Research

19 pages, 1258 KiB  
Review
Synaptic Plasticity Dysfunctions in the Pathophysiology of 22q11 Deletion Syndrome: Is There a Role for Astrocytes?
by Eva Cristina de Oliveira Figueiredo, Bianca Maria Bondiolotti, Anthony Laugeray and Paola Bezzi
Int. J. Mol. Sci. 2022, 23(8), 4412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084412 - 16 Apr 2022
Cited by 8 | Viewed by 3027
Abstract
The 22q11 deletion syndrome (DS) is the most common microdeletion syndrome in humans and gives a high probability of developing psychiatric disorders. Synaptic and neuronal malfunctions appear to be at the core of the symptoms presented by patients. In fact, it has long [...] Read more.
The 22q11 deletion syndrome (DS) is the most common microdeletion syndrome in humans and gives a high probability of developing psychiatric disorders. Synaptic and neuronal malfunctions appear to be at the core of the symptoms presented by patients. In fact, it has long been suggested that the behavioural and cognitive impairments observed in 22q11DS are probably due to alterations in the mechanisms regulating synaptic function and plasticity. Often, synaptic changes are related to structural and functional changes observed in patients with cognitive dysfunctions, therefore suggesting that synaptic plasticity has a crucial role in the pathophysiology of the syndrome. Most interestingly, among the genes deleted in 22q11DS, six encode for mitochondrial proteins that, in mouse models, are highly expressed just after birth, when active synaptogenesis occurs, therefore indicating that mitochondrial processes are strictly related to synapse formation and maintenance of a correct synaptic signalling. Because correct synaptic functioning, not only requires correct neuronal function and metabolism, but also needs the active contribution of astrocytes, we summarize in this review recent studies showing the involvement of synaptic plasticity in the pathophysiology of 22q11DS and we discuss the relevance of mitochondria in these processes and the possible involvement of astrocytes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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26 pages, 950 KiB  
Review
Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies
by Ahmed Eltokhi, Andrea Santuy, Angel Merchan-Perez and Rolf Sprengel
Int. J. Mol. Sci. 2021, 22(1), 59; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010059 - 23 Dec 2020
Cited by 31 | Viewed by 5908
Abstract
The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed. Both disorders are associated with molecular and ultrastructural alterations that affect synaptic plasticity and thus the molecular and physiological basis of learning and memory. [...] Read more.
The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed. Both disorders are associated with molecular and ultrastructural alterations that affect synaptic plasticity and thus the molecular and physiological basis of learning and memory. Altered synaptic plasticity, accompanied by changes in protein synthesis and trafficking of postsynaptic proteins, as well as structural modifications of excitatory synapses, are critically involved in the postnatal development of the mammalian nervous system. In this review, we summarize glutamatergic alterations and ultrastructural changes in synapses in schizophrenia and autism spectrum disorder of genetic or drug-related origin, and briefly comment on the possible reversibility of these neuropsychiatric disorders in the light of findings in regular synaptic physiology. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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Review
Roadmap for Stroke: Challenging the Role of the Neuronal Extracellular Matrix
by Ciro De Luca, Assunta Virtuoso, Nicola Maggio, Sara Izzo, Michele Papa and Anna Maria Colangelo
Int. J. Mol. Sci. 2020, 21(20), 7554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207554 - 13 Oct 2020
Cited by 6 | Viewed by 2889
Abstract
Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to [...] Read more.
Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathophysiology, relating the injury to the NVU with the pervasive metabolic failure, inflammatory response and modifications of the NECM. The available data will be used to build a protein–protein interaction (PPI) map starting with 38 proteins involved in stroke pathophysiology, taking into account the timeline of damage and the co-expression scores of their RNA patterns The application of the proposed network could lead to a more accurate design of translational experiments aiming at improving both the therapy and the rehabilitation processes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity 2.0: Dynamic Changes in Neurons Functions, Physiological and Pathological Process)
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