PTX-induced hyperexcitability affects dendritic shape and GABAergic synapse density but not synapse distribution during Manduca postembryonic motoneuron development

To reveal the pathomechanisms of glaucoma, a common cause of blindness, suitable animal models are needed. As previously shown, retinal ganglion cell and optic nerve degeneration occur in βB1-CTGF mice. Here, we aimed to determine possible apoptotic mechanisms and degeneration of different retinal cells. Hence, retinae were processed for immunohistology (n = 5–9/group) and quantitative real-time PCR analysis (n = 5–7/group) in 5- and 10-week-old βB1-CTGF and wildtype controls. We noted significantly more cleaved caspase 3+ cells in βB1-CTGF retinae at 5 (p = 0.005) and 10 weeks (p = 0.02), and a significant upregulation of Casp3 and Bax/Bcl2 mRNA levels (p < 0.05). Furthermore, more terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL+) cells were detected in transgenic mice at 5 (p = 0.03) and 10 weeks (p = 0.02). Neurofilament H staining (p = 0.01) as well as Nefh (p = 0.02) and Tubb3 (p = 0.009) mRNA levels were significantly decreased at 10 weeks. GABAergic synapse intensity was lower at 5 weeks, while no alterations were noted at 10 weeks. The glutamatergic synapse intensity was decreased at 5 (p = 0.007) and 10 weeks (p = 0.01). No changes were observed for bipolar cells, photoreceptors, and macroglia. We conclude that apoptotic processes and synapse loss precede neuronal death in this model. This slow progression rate makes the βB1-CTGF mice a suitable model to study primary open-angle glaucoma.

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The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum

Cell Death and Differentiation ◽

10.1038/s41418-021-00774-3 ◽

2021 ◽

Author(s):

Fei Wang ◽

Qianqian Wang ◽

Baowei Liu ◽

Lisheng Mei ◽

Sisi Ma ◽

...

Keyword(s):

Noncoding Rna ◽

Cerebellar Atrophy ◽

Synaptic Activity ◽

Motor Dysfunction ◽

Cerebellar Development ◽

Full Spectrum ◽

Density Reduction ◽

Adult Mice ◽

Synapse Density ◽

And Function

AbstractThe brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

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BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions

The Journal of Cell Biology ◽

10.1083/jcb.200601087 ◽

2006 ◽

Vol 174 (2) ◽

pp. 289-299 ◽

Cited By ~ 115

Author(s):

Shernaz X. Bamji ◽

Beatriz Rico ◽

Nikole Kimes ◽

Louis F. Reichardt

Keyword(s):

Synaptic Vesicle ◽

Synaptic Vesicles ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Synapse Formation ◽

Time Lapse ◽

Synapse Density ◽

Vesicle Mobility ◽

Small Clusters ◽

Vertebrate Central Nervous System

Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles “splitting” away from synaptic sites. We demonstrate that BDNF's ability to mobilize synaptic vesicle clusters depends on the dissociation of cadherin–β-catenin adhesion complexes that occurs after tyrosine phosphorylation of β-catenin. Artificially maintaining cadherin–β-catenin complexes in the presence of BDNF abolishes the BDNF-mediated enhancement of synaptic vesicle mobility, as well as the longer-term BDNF-mediated increase in synapse number. Together, this data demonstrates that the disruption of cadherin–β-catenin complexes is an important molecular event through which BDNF increases synapse density in cultured hippocampal neurons.

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Receptive field of the retinal bipolar cell: a pharmacological study in the tiger salamander

Journal of Neurophysiology ◽

10.1152/jn.1996.76.3.2005 ◽

1996 ◽

Vol 76 (3) ◽

pp. 2005-2019 ◽

Cited By ~ 42

Author(s):

W. A. Hare ◽

W. G. Owen

Keyword(s):

Receptive Field ◽

Gaba Receptors ◽

Bipolar Cell ◽

Horizontal Cell ◽

Pharmacological Study ◽

Bipolar Cells ◽

Horizontal Cells ◽

Gaba Uptake ◽

Gamma Aminobutyric Acid ◽

Gabaergic Synapse

1. It is widely believed that signals contributing to the receptive field surrounds of retinal bipolar cells pass from horizontal cells to bipolar cells via GABAergic synapses. To test this notion, we applied gamma-aminobutyric acid (GABA) agonists and antagonists to isolated, perfused retinas of the salamander Ambystoma tigrinum while recording intracellularly from bipolar cells, horizontal cells, and photoreceptors. 2. As we previously reported, administration of the GABA analogue D-aminovaleric acid in concert with picrotoxin did not block horizontal cell responses or the center responses of bipolar cells but blocked the surround responses of both on-center and off-center bipolar cells. 3. Surround responses were not blocked by the GABA, antagonists picrotoxin or bicuculline, the GABAB agonist baclofen or the GABAB antagonist phaclofen, and the GABAC antagonists picrotoxin or cis-4-aminocrotonic acid. Combinations of these drugs were similarly ineffective. 4. GABA itself activated a powerful GABA uptake mechanism in horizontal cells for which nipecotic acid is a competitive agonist. It also activated, both in horizontal cells and bipolar cells, large GABAA conductances that shunted light responses but that could be blocked by picrotoxin or bicuculline. 5. GABA, administered together with picrotoxin to block the shunting effect of GABAA activation, did not eliminate bipolar cell surround responses at concentrations sufficient to saturate the known types of GABA receptors. 6. Surround responses were not blocked by glycine or its antagonist strychnine, or by combinations of drugs designed to eliminate GABAergic and glycinergic pathways simultaneously. 7. Although we cannot fully discount the involvement of a novel GABAergic synapse, the simplest explanation of our findings is that the primary pathway mediating the bipolar cell's surround is neither GABAergic nor glycinergic.

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Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1011824108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 379-384 ◽

Cited By ~ 116

Author(s):

Shiva K. Tyagarajan ◽

Himanish Ghosh ◽

Gonzalo E. Yévenes ◽

Irina Nikonenko ◽

Claire Ebeling ◽

...

Keyword(s):

Synaptic Plasticity ◽

Hippocampal Neurons ◽

Glycogen Synthase ◽

Phosphorylation Site ◽

Scaffolding Protein ◽

Scaffolding Proteins ◽

Gabaergic Synapse ◽

Gabaergic Synapses

Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca2+-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium.

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The space where aging acts: focus on the GABAergic synapse

Aging Cell ◽

10.1111/acel.12605 ◽

2017 ◽

Vol 16 (4) ◽

pp. 634-643 ◽

Cited By ~ 50

Author(s):

Aleksandra Rozycka ◽

Monika Liguz-Lecznar

Keyword(s):

Gabaergic Synapse

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Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

10.1101/2021.07.21.453252 ◽

2021 ◽

Author(s):

Jessica L Bolton ◽

Annabel K Short ◽

Shivashankar Othy ◽

Cassandra L Kooiker ◽

Manlin Shao ◽

...

Keyword(s):

Stress Responses ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Mental Illnesses ◽

Excitatory Synapses ◽

Process Dynamics ◽

Brain Circuits ◽

Synapse Density ◽

And Function

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

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