scholarly journals Csmd2 is a Synaptic Transmembrane Protein that Interacts with PSD-95

2018 ◽  
Author(s):  
Mark A Gutierrez ◽  
Brett E Dwyer ◽  
Santos J Franco
Keyword(s):  
Transmembrane Protein ◽  
Copy Number Variants ◽  
Plexiform Layer ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Inhibitory Neurons ◽  
Inner Plexiform Layer ◽  
Tail Domain ◽  
Synaptic Targeting ◽  
Ribbon Synapses

AbstractMutations and copy number variants of the Cub and Sushi Multiple Domains 2 (CSMD2) gene are associated with schizophrenia and autism spectrum disorder. CSMD2 is a single-pass transmembrane protein with a large extracellular domain comprising repeats of Cub and Sushi domains. Although the biological functions of CSMD2 have not been studied, the association between CSMD2 variants and cognitive function suggest that it may have a role in brain development or function. In this study, we show that mouse Csmd2 is expressed in excitatory and inhibitory neurons in the brain. Csmd2 protein exhibits a somatodendritic localization in the neocortex and hippocampus, with smaller puncta localizing further out in the neuropil. We show that many of these Csmd2 puncta co-localize with the synaptic protein PSD-95. Using immunohistochemical and biochemical methods, we further demonstrate that Csmd2 localizes to dendritic spines and is enriched in the postsynaptic density. We also find Csmd2 at ribbon synapses of the inner plexiform layer of the retina, suggesting a broader synaptic function of Csmd2 in the central nervous system. Finally, we show that the cytoplasmic tail domain of Csmd2 interacts with synaptic scaffolding proteins of the membrane-associated guanylate kinase (MAGUK) family. The association between Csmd2 and MAGUK member PSD-95 is dependent on a PDZ-binding domain on the Csmd2 tail, which is also required for synaptic targeting of Csmd2. Together, these results point toward a function for Csmd2 in dendrites and synapses, which may account for its association with several psychiatric disorders.

Synaptic Organization of an organotypic slice culture of the mammalian retina

1996 ◽  
Vol 13 (4) ◽  
pp. 759-771 ◽  
Author(s):  
Marco Sassoè-Pognetto ◽  
Andreas Feigenspan ◽  
Joachim Bormann ◽  
Heinz Wässle
Keyword(s):  
Hot Spots ◽  
Plexiform Layer ◽  
Slice Culture ◽  
Inner Plexiform Layer ◽  
Synaptic Organization ◽  
Glycine Receptors ◽  
Ribbon Synapses ◽  
Organotypic Slice Culture ◽  
Transmitter Receptors

AbstractVertical Slices of postnatal day 6 (P6) rat retina were cut and cultured using the roller-tube technique. The organotypic differentiation during a culture period of up to 30 days has been described in a previous study (Feigenspan et al., 1993a). Here we concentrated on the synaptic organization in the retinal slice culture. Electron microscopy revealed the presence of ribbon synapses in the outer plexiform layer and conventional and ribbon syanpses in the inner plexiform layer. Immunofluroscence with antibodies that recognize specific subunits of GABAA or glycine receptors revealed a punctuate distribution of the receptors. They were aggregated in “hot spots” that correspond to a concentration of receptors at postsynaptic sites. Different isoforms of GABAA and glycine receptors occured in the slice cultures. The experiments show that there is a differentiation of synapses and a diversity of transmitter receptors in the slice cultures that is comparable to the in vivo retina.

Ribbon Synapses Formed at the Axon of the Calbindin-Immunoreactive ON Cone Bipolar Cell in OFF Sublamina of the Inner Plexiform Layer in the Rabbit Retina

2011 ◽  
Vol 24 (4) ◽  
pp. 195
Author(s):  
Tae Hyung Koo ◽  
Hong Lim Kim ◽  
Ji Hyun Jeon ◽  
Eo Jin Jeong ◽  
Myung Hoon Chun ◽  
...  
Keyword(s):  
Bipolar Cell ◽  
Plexiform Layer ◽  
Inner Plexiform Layer ◽  
Rabbit Retina ◽  
Ribbon Synapses

Morphological differentiation of bipolar cells in the ferret retina

1999 ◽  
Vol 16 (6) ◽  
pp. 1133-1144 ◽  
Author(s):  
E.D. MILLER ◽  
M.N. TRAN ◽  
G.-K. WONG ◽  
D.M. OAKLEY ◽  
R.O.L. WONG
Keyword(s):  
Visual Processing ◽  
Plexiform Layer ◽  
Morphological Differentiation ◽  
Bipolar Cells ◽  
Inner Plexiform Layer ◽  
Axon Terminals ◽  
Ribbon Synapses ◽  
Rod Bipolar Cells ◽  
Cone Bipolar Cells ◽  
Dye Labeling

Bipolar cells are not only important for visual processing but input from these cells may underlie the reorganization of ganglion cell dendrites in the inner plexiform layer (IPL) during development. Because little is known about the development of bipolar cells, here we have used immunocytochemical markers and dye labeling to identify and follow their differentiation in the neonatal ferret retina. Putative cone bipolar cells were immunoreacted for calbindin and recoverin, and rod bipolar cells were immunostained for protein kinase C (PKC). Our results show that calbindin-immunoreactive cone bipolar cells appear at postnatal day 15 (P15), at which time their axonal terminals are already localized to the inner half of the IPL. By contrast, recoverin-immunoreactive cells with terminals in the IPL are present at birth, but many of these cells may be immature photoreceptors. By the second postnatal week, recoverin-positive cells resembling cone bipolar cells were clearly present, and with increasing age, two distinct strata of immunolabeled processes occupied the IPL. PKC-containing rod bipolar cells emerged by the fourth postnatal week and at this age have stratified arbors in the inner IPL. The early bias of bipolar axonal arbors in terminating in the inner or outer half of the IPL is confirmed by dye labeling of cells with somata in the inner nuclear layer. At P10, several days before ribbon synapses have been previously observed in the ferret IPL, the axon terminals of all dye-labeled bipolar cells were clearly stratified. The results suggest that bipolar cells could provide spatially localized interactions that are suitable for guiding dendritic lamination in the inner retina.

scholarly journals Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

2018 ◽  
Author(s):  
Michaela Fenckova ◽  
Lenke Asztalos ◽  
Pavel Cizek ◽  
Euginia L. Singgih ◽  
Laura E.R. Blok ◽  
...  
Keyword(s):  
De Novo ◽  
Cholinergic Neurons ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Inhibitory Neurons ◽  
Molecular Processes ◽  
Simons Simplex Collection ◽  
Id Genes ◽  
Gene Ontologies

AbstractBackgroundAlthough habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood.MethodsWe manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.ResultsWe identified more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.ConclusionsOur work demonstrates the relevance of habituation learning to autism, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.

scholarly journals Synaptic connections of amacrine cells containing vesicular glutamate transporter 3 in baboon retinas

2015 ◽  
Vol 32 ◽  
Author(s):  
DAVID W. MARSHAK ◽  
ALICE Z. CHUANG ◽  
DREW M. DOLINO ◽  
ROY A. JACOBY ◽  
WEILEY S. LIU ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Glutamate Transporter ◽  
Plexiform Layer ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Inhibitory Synapses ◽  
Inner Plexiform Layer ◽  
Vesicular Glutamate Transporter ◽  
Synaptic Connections ◽  
Ribbon Synapses

AbstractThe goals of these experiments were to describe the morphology and synaptic connections of amacrine cells in the baboon retina that contain immunoreactive vesicular glutamate transporter 3 (vGluT3). These amacrine cells had the morphology characteristic of knotty bistratified type 1 cells, and their dendrites formed two plexuses on either side of the center of the inner plexiform layer. The primary dendrites received large synapses from amacrine cells, and the higher-order dendrites were both pre- and postsynaptic to other amacrine cells. Based on light microscopic immunolabeling results, these include AII cells and starburst cells, but not the polyaxonal amacrine cells tracer-coupled to ON parasol ganglion cells. The vGluT3 cells received input from ON bipolar cells at ribbon synapses and made synapses onto OFF bipolar cells, including the diffuse DB3a type. Many synapses from vGluT3 cells onto retinal ganglion cells were observed in both plexuses. At synapses where vGluT3 cells were presynaptic, two types of postsynaptic densities were observed; there were relatively thin ones characteristic of inhibitory synapses and relatively thick ones characteristic of excitatory synapses. In the light microscopic experiments with Neurobiotin-injected ganglion cells, vGluT3 cells made contacts with midget and parasol ganglion cells, including both ON and OFF types. Puncta containing immunoreactive gephyrin, an inhibitory synapse marker, were found at appositions between vGluT3 cells and each of the four types of labeled ganglion cells. The vGluT3 cells did not have detectable levels of immunoreactive γ-aminobutyric acid (GABA) or immunoreactive glycine transporter 1. Thus, the vGluT3 cells would be expected to have ON responses to light and make synapses onto neurons in both the ON and the OFF pathways. Taken with previous results, these findings suggest that vGluT3 cells release glycine at some of their output synapses and glutamate at others.

scholarly journals Altered visual function in a larval zebrafish knockout of neurodevelopmental risk gene pdzk1

2020 ◽  
Author(s):  
Jiaheng Xie ◽  
Patricia R. Jusuf ◽  
Bang V. Bui ◽  
Stefanie Dudczig ◽  
Patrick T. Goodbourn
Keyword(s):  
Visual Function ◽  
Genome Wide Association Study ◽  
Frequency Tuning ◽  
Gain Control ◽  
Plexiform Layer ◽  
Autism Spectrum ◽  
Inner Plexiform Layer ◽  
Optomotor Response ◽  
Visual Contrast ◽  
A Genome

AbstractThe human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study (GWAS) identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including post-synaptic density 95 (PSD-95), N-methyl-D-aspartate receptors (NMDAR), corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptors. To elucidate the role of PDZK1, we generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioural and functional levels using the optomotor response (OMR) and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1 and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks and 8 weeks of age. Relative to wild-type, pdzk1-KO larvae showed spatial-frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). However, these functional differences were not associated with gross synaptic or morphological retinal phenotypes. The findings corroborate a role for pdzk1 in visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behaviour.

Synaptic connectivity of two types of recoverin-labeled cone bipolar cells and glutamic acid decarboxylase immunoreactive amacrine cells in the inner plexiform layer of the rat retina

1999 ◽  
Vol 16 (4) ◽  
pp. 791-800 ◽  
Author(s):  
MYUNG-HOON CHUN ◽  
IN-BEOM KIM ◽  
SU-JA OH ◽  
JIN-WOONG CHUNG
Keyword(s):  
Amacrine Cell ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Acid Decarboxylase ◽  
Inner Plexiform Layer ◽  
Rat Retina ◽  
Ribbon Synapses ◽  
Cell Processes ◽  
Cone Bipolar Cells

We investigated the synaptic connectivity of two populations of recoverin-labeled bipolar cells and GABAergic neurons in the inner plexiform layer (IPL) of the rat retina. Two types of cone bipolar cells, type 2 and type 8, were stained with anti-recoverin antibodies, and GABAergic neurons were stained with anti-glutamic acid decarboxylase (GAD) antibodies. Type 2 cone bipolar axons received synaptic input from amacrine cell processes in 177 cases; among these amacrine cell processes, 92 processes (52.0%) were GAD-like immunoreactive. A total of 159 amacrine cell processes, which are presynaptic to type 8 cone bipolar cells, were observed. Among these processes, 117 processes (73.6%) were GAD-like immunoreactive. The postsynaptic elements at the ribbon synapses of recoverin-labeled cone bipolar cells were observed in 482 processes. In both type 2 and type 8 cone bipolar cells, the major output was to amacrine cell processes. At the ribbon synapses of the type 2 cone bipolar cells, 224 of the postsynaptic profiles were amacrine cell processes, 97 processes (43.3%) were GAD-like immunoreactive. In type 8 cone bipolar cells, 45 processes (30.2%) of 149 amacrine cell processes were GAD-like immunoreactive. Our results provide morphological evidence that GABA is a major transmitter involved in the visual processing of type 2 and 8 cone bipolar cells and GABA may have a stronger influence on type 8 cone bipolar cells than type 2 cone bipolar cells in the IPL of the rat retina.

Synaptic organization of the inner plexiform layer of the retina of Xenopus laevis

1978 ◽  
Vol 201 (1142) ◽  
pp. 57-72 ◽  
Keyword(s):  
Xenopus Laevis ◽  
South African ◽  
Plexiform Layer ◽  
Uranyl Acetate ◽  
Inner Plexiform Layer ◽  
Lead Citrate ◽  
Synaptic Organization ◽  
Ribbon Synapses ◽  
Layer I ◽  
Clawed Frog

The inner plexiform layer (i. p. l.) of the retina of the South African clawed frog, Xenopus laevis , was studied by electron microscopy. Photomicrographs of single sections revealed synaptic morphologies comparable to those in other vertebrate retinae. In a partial serial reconstruction of a bipolar terminal, however, some unusual arrangements were found. The bipolar terminal made some synapses that at first examination appeared much like conventional synapses, but subsequent sections always revealed an extremely small ribbon. Many of the ribbon synapses were found to contact more than two postsynaptic processes; up to six pro­cesses postsynaptic to one ribbon contact were seen. A reciprocal synapse was not evident at each ribbon synapse. Montages of the entire width of the inner plexiform layer were constructed from sections cut from four different locations across the retina. The numbers of conventional and ribbon synapses per unit volume of tissue were determined. The synaptic densities found in Xenopus were much lower than those reported for other frogs. Differences in synaptic densities from the four locations were found to be statistically insignificant. The overall amacrine/bipolar synapse ratio was 6.8/1. The synaptic den­sities in the inner plexiform layer did not change when the tissue was stained with lead citrate alone rather than with uranyl acetate and lead citrate. The functional significance of the morphological and quantitative synaptic arrangements in Xenopus i. p. l. is discussed, and the synaptic organization is compared to that of other amphibia and vertebrates.

Subcellular localization of neuronal nitric oxide synthase in turtle retina: Electron immunocytochemistry

2001 ◽  
Vol 18 (6) ◽  
pp. 949-960 ◽  
Author(s):  
LUXIANG CAO ◽  
WILLIAM D. ELDRED
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Bipolar Cell ◽  
Plexiform Layer ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Inner Plexiform Layer ◽  
Ribbon Synapses ◽  
Cell Processes ◽  
Oxide Synthase

Recent studies imaging nitric oxide (NO) production in the retina have indicated a much wider distribution of NO production than would be suggested by previous light-microscopic localizations of neuronal nitric oxide synthase (nNOS). To help resolve this discrepancy, the present study analyzed the ultrastructural localization of nNOS-like immunoreactivity (-LI) in all layers of the retina. In the ellipsoids of rod photoreceptors and the accessory elements of double cones, nNOS-LI was associated with some atypical mitochondria. In the outer plexiform layer, nNOS-LI was in some postsynaptic horizontal and bipolar cell processes at photoreceptor ribbon synapses. In some amacrine and ganglion cell somata, nNOS-LI was diffusely localized in the cytoplasm and associated with the endoplasmic reticulum. In the inner plexiform layer, nNOS-LI diffusely filled some amacrine cell processes, while in other amacrine cells nNOS-LI was selectively localized at the presynaptic specializations of conventional synapses. Neuronal NOS-LI was also found at membrane specializations in bipolar cell terminals that were distinct from their normal ribbon synapses. Finally, some nNOS-LI was found in mitochondria in Müller cells. The diverse subcellular localizations of nNOS-LI indicates that NO may play distinct functional roles in many retinal cells, which correlates well with the widespread NO production found in previous NO imaging studies.

Inner Retinal Morphology and Visual Outcomes in Idiopathic Epiretinal Membrane Surgery: A Retrospective Optical Coherence Tomography Study

2021 ◽  
pp. 247412642198961
Author(s):  
Ioannis S. Dimopoulos ◽  
Michael Dollin
Keyword(s):  
Optical Coherence Tomography ◽  
Epiretinal Membrane ◽  
Strong Predictor ◽  
Plexiform Layer ◽  
Inner Plexiform Layer ◽  
Optical Coherence ◽  
Visual Outcomes ◽  
Retinal Pathology

Purpose: Epiretinal membrane (ERM) is a common retinal finding for patients older than 50 years. Disorganization of the retinal inner layers (DRIL) has emerged as a novel predictor of poor visual acuity (VA) in eyes with inner retinal pathology. The aim of our study is to correlate preoperative DRIL with visual outcomes after ERM surgery. Methods: Medical records and optical coherence tomography (OCT) images of 81 pseudophakic patients who underwent treatment of idiopathic ERM were reviewed. Preoperative DRIL on OCT was correlated with VA at baseline and at 3 and 6 months after ERM surgery. DRIL was defined as the loss of distinction between the ganglion cell–inner plexiform layer complex, inner nuclear layer, and outer plexiform layer. DRIL severity was based on its extent within the central 2-mm region of a transfoveal B-scan (absent/mild: <one-third, severe: >one-third horizontal width). Results: Review of preoperative OCT showed severe DRIL in 41% and absent/mild DRIL in 59%. Severe DRIL was associated with worse baseline VA ( P < .001). Preoperative VA and DRIL status at baseline were both predictors of postoperative VA at follow-up time points ( P < .001). Severe DRIL was associated with significantly less improvement in VA at 6 months (–0.23 logMAR for absent/mild vs –0.14 for severe DRIL). Conclusions: Presence of severe preoperative DRIL correlates with worse baseline VA in patients with ERM and reduced VA improvement at 6 months. DRIL can be a strong predictor of long-term poor visual outcomes in ERM surgery.

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