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Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 15912

Special Issue Editor

Dr. Eva Kiss

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Guest Editor
Department of Cellular and Molecular Biology, University of Medicine, Pharmacy, Science and Technology “G.E. Palade” of Târgu Mures, Târgu Mureș, Romania
Interests: Alzheimer's disease; inhibitory synapses; gephyrin; neurodegeneration; neuorinflammation; microglia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The still incompletely understood pathogenesis of neurodegenerative diseases represents one important reason previous therapeutic approaches failed to effectively cure or delay their progression. Synaptic dysfunction, including altered synaptic plasticity, seems to be a central pathophysiological process in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Research in recent years has strongly supported the involvement of GABAergic neurotransmission in both early and late pathogenesis of these groups of diseases. The GABAergic system might undergo dynamic remodeling and play different roles in the pathology at various disease stages. This seems to include stage-dependent alterations in presynaptic and postsynaptic components of inhibitory synapses and particularly scaffolding, anchoring and supporting proteins of GABAA receptors which influence the plasticity of the GABAergic system. The modulation of GABAergic neurotransmission through targeting inhibitory synapse proteins and their interactions (e.g., receptor–scaffold protein interactions) was proposed as a promising pharmacological strategy to normalize synapse dynamics and restore cognitive function.

This Special Issue of IJMS encourages primarily original research articles and short communications that expand present and identify new perspectives and molecular details for a more profound understanding of the GABAergic system along neurodegeneration. Review articles covering the most recent discoveries in this area and new therapeutic approaches targeting GABAergic synapses are also welcome.

Dr. Eva Kiss
Guest Editor

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Keywords

  • neurodegeneration
  • inhibitory synapse
  • synaptic plasticity
  • GABAARs
  • scaffolding proteins
  • animal models
  • imaging

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Published Papers (5 papers)

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Research

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22 pages, 7535 KiB  
Article
Loss of Extrasynaptic Inhibitory Glycine Receptors in the Hippocampus of an AD Mouse Model Is Restored by Treatment with Artesunate
by Jochen Kuhse, Femke Groeneweg, Stefan Kins, Karin Gorgas, Ralph Nawrotzki, Joachim Kirsch and Eva Kiss
Int. J. Mol. Sci. 2023, 24(5), 4623; https://doi.org/10.3390/ijms24054623 - 27 Feb 2023
Cited by 6 | Viewed by 2268
Abstract
Alzheimer’s disease (AD) is characterized by synaptic failure and neuronal loss. Recently, we demonstrated that artemisinins restored the levels of key proteins of inhibitory GABAergic synapses in the hippocampus of APP/PS1 mice, a model of cerebral amyloidosis. In the present study, we analyzed [...] Read more.
Alzheimer’s disease (AD) is characterized by synaptic failure and neuronal loss. Recently, we demonstrated that artemisinins restored the levels of key proteins of inhibitory GABAergic synapses in the hippocampus of APP/PS1 mice, a model of cerebral amyloidosis. In the present study, we analyzed the protein levels and subcellular localization of α2 and α3 subunits of GlyRs, indicated as the most abundant receptor subtypes in the mature hippocampus, in early and late stages of AD pathogenesis, and upon treatment with two different doses of artesunate (ARS). Immunofluorescence microscopy and Western blot analysis demonstrated that the protein levels of both α2 and α3 GlyRs are considerably reduced in the CA1 and the dentate gyrus of 12-month-old APP/PS1 mice when compared to WT mice. Notably, treatment with low-dose ARS affected GlyR expression in a subunit-specific way; the protein levels of α3 GlyR subunits were rescued to about WT levels, whereas that of α2 GlyRs were not affected significantly. Moreover, double labeling with a presynaptic marker indicated that the changes in GlyR α3 expression levels primarily involve extracellular GlyRs. Correspondingly, low concentrations of artesunate (≤1 µM) also increased the extrasynaptic GlyR cluster density in hAPPswe-transfected primary hippocampal neurons, whereas the number of GlyR clusters overlapping presynaptic VIAAT immunoreactivities remained unchanged. Thus, here we provide evidence that the protein levels and subcellular localization of α2 and α3 subunits of GlyRs show regional and temporal alterations in the hippocampus of APP/PS1 mice that can be modulated by the application of artesunate. Full article
(This article belongs to the Special Issue Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases)
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19 pages, 4116 KiB  
Article
Reorganization of Parvalbumin Immunopositive Perisomatic Innervation of Principal Cells in Focal Cortical Dysplasia Type IIB in Human Epileptic Patients
by Cecília Szekeres-Paraczky, Péter Szocsics, Loránd Erőss, Dániel Fabó, László Mód and Zsófia Maglóczky
Int. J. Mol. Sci. 2022, 23(9), 4746; https://doi.org/10.3390/ijms23094746 - 25 Apr 2022
Cited by 2 | Viewed by 2538
Abstract
Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. As several studies have revealed, the abnormal functioning of the perisomatic inhibitory system may play a role in the onset of seizures. Therefore, we wanted to investigate whether changes [...] Read more.
Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. As several studies have revealed, the abnormal functioning of the perisomatic inhibitory system may play a role in the onset of seizures. Therefore, we wanted to investigate whether changes of perisomatic inhibitory inputs are present in FCD. Thus, the input properties of abnormal giant- and control-like principal cells were examined in FCD type IIB patients. Surgical samples were compared to controls from the same cortical regions with short postmortem intervals. For the study, six subjects were selected/each group. The perisomatic inhibitory terminals were quantified in parvalbumin and neuronal nuclei double immunostained sections using a confocal fluorescent microscope. The perisomatic input of giant neurons was extremely abundant, whereas control-like cells of the same samples had sparse inputs. A comparison of pooled data shows that the number of parvalbumin-immunopositive perisomatic terminals contacting principal cells was significantly larger in epileptic cases. The analysis showed some heterogeneity among epileptic samples. However, five out of six cases had significantly increased perisomatic input. Parameters of the control cells were homogenous. The reorganization of the perisomatic inhibitory system may increase the probability of seizure activity and might be a general mechanism of abnormal network activity. Full article
(This article belongs to the Special Issue Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases)
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27 pages, 6171 KiB  
Article
Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex
by Estilla Zsófia Tóth, Felicia Gyöngyvér Szabó, Ágnes Kandrács, Noémi Orsolya Molnár, Gábor Nagy, Attila G. Bagó, Loránd Erőss, Dániel Fabó, Boglárka Hajnal, Bence Rácz, Lucia Wittner, István Ulbert and Kinga Tóth
Int. J. Mol. Sci. 2022, 23(1), 202; https://doi.org/10.3390/ijms23010202 - 24 Dec 2021
Cited by 2 | Viewed by 3635
Abstract
Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in [...] Read more.
Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in epilepsy have been thoroughly investigated. This paper demonstraits how parvalbumin (PV)- and type 1 cannabinoid receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies, and their role in synchronous population events spontaneously emerging in the human epileptic and non-epileptic neocortex, in vitro. Quantitative electron microscopy showed that the overall, PV+ and CB1R+ somatic inhibitory inputs remained unchanged in focal cortical epilepsy. On the contrary, the size of PV-stained synapses increased, and their number decreased in epileptic samples, in synchrony generating regions. Pharmacology demonstrated—in conjunction with the electron microscopy—that although both perisomatic cell types participate, PV+ cells have stronger influence on the generation of population activity in epileptic samples. The somatic inhibitory input of neocortical pyramidal cells remained almost intact in epilepsy, but the larger and consequently more efficient somatic synapses might account for a higher synchrony in this neuron population. This, together with epileptic hyperexcitability, might make a cortical region predisposed to generate or participate in hypersynchronous events. Full article
(This article belongs to the Special Issue Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases)
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Review

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28 pages, 1868 KiB  
Review
Inhibitory Synaptic Influences on Developmental Motor Disorders
by Matthew J. Fogarty
Int. J. Mol. Sci. 2023, 24(8), 6962; https://doi.org/10.3390/ijms24086962 - 9 Apr 2023
Cited by 3 | Viewed by 2412
Abstract
During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to [...] Read more.
During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to discuss the differences in limb and respiratory neuromotor control. We then investigate the influences that GABAergic and glycinergic neurotransmission has on two major developmental neuromotor disorders: Rett syndrome and spastic cerebral palsy. We present these two syndromes in order to contrast the approaches to disease mechanism and therapy. While both conditions have motor dysfunctions at their core, one condition Rett syndrome, despite having myriad symptoms, has scientists focused on the breathing abnormalities and their alleviation—to great clinical advances. By contrast, cerebral palsy remains a scientific quagmire or poor definitions, no widely adopted model and a lack of therapeutic focus. We conclude that the sheer abundance of diversity of inhibitory neurotransmitter targets should provide hope for intractable conditions, particularly those that exhibit broad spectra of dysfunction—such as spastic cerebral palsy and Rett syndrome. Full article
(This article belongs to the Special Issue Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases)
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15 pages, 1411 KiB  
Review
Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders
by Snježana Radulović, Sowmya Sunkara, Christa Maurer and Gerd Leitinger
Int. J. Mol. Sci. 2021, 22(22), 12470; https://doi.org/10.3390/ijms222212470 - 18 Nov 2021
Cited by 1 | Viewed by 3961
Abstract
Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in [...] Read more.
Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders. Full article
(This article belongs to the Special Issue Changes in Inhibitory Synapse Composition and Plasticity along the Progression of Neurodegenerative Diseases)
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