PRICKLE1 Interaction with SYNAPSIN I Reveals a Role in Autism Spectrum Disorders

Paemka, Lily; Mahajan, Vinit B.; Skeie, Jessica M.; Sowers, Levi P.; Ehaideb, Salleh N.; Gonzalez‐Alegre, Pedro; Sasaoka, Toshikuni; Tao, Hirotaka; Miyagi, Asuka; Ueno, Naoto; Takao, Keizo; Miyakawa, Tsuyoshi; Wu, Shu; Darbro, Benjamin W.; Ferguson, Polly J.; Pieper, Andrew A.; Britt, Jeremiah K.; Wemmie, John A.; Rudd, Danielle S.; Wassink, Thomas H.; El‐Shanti, Hatem; Mefford, Heather C; Carvill, Gemma L.; Manak, J. Robert; Bassuk, Alexander G.

doi:10.1371/journal.pone.0080737

Cited by 41 publications

(57 citation statements)

References 58 publications

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“…Vangl2 and Prickle2 also bind and promote postsynaptic clustering of PSD95, critical for maintenance of synaptic integrity [199,227,228]. Prickle1 was found to regulate synaptogenesis and synaptic vesicle trafficking through a direct interaction with synapsin1 (Syn1) [229]; the synapsin protein family have important roles in synapse formation and neurotransmitter release and have previously been implicated in the pathogenesis of psychiatric disorders [230,231,232,233,234,235,236]. Indeed, Prickle1 +/- mice exhibit ASD-like behaviors, and expression of a mutant form of Prickle in cultured cells phenocopies the vesicle trafficking defect observed with aberrant Syn1 function [229].…”

Section: Synapse Formation and Functionmentioning

confidence: 99%

“…Prickle1 was found to regulate synaptogenesis and synaptic vesicle trafficking through a direct interaction with synapsin1 (Syn1) [229]; the synapsin protein family have important roles in synapse formation and neurotransmitter release and have previously been implicated in the pathogenesis of psychiatric disorders [230,231,232,233,234,235,236]. Indeed, Prickle1 +/- mice exhibit ASD-like behaviors, and expression of a mutant form of Prickle in cultured cells phenocopies the vesicle trafficking defect observed with aberrant Syn1 function [229]. While upstream Wnt ligands involved in these events remain to be identified, these studies provide additional evidence that components of the Wnt/PCP pathway are critical contributors to synapse formation and function.…”

Section: Synapse Formation and Functionmentioning

confidence: 99%

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Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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Section: Synapse Formation and Functionmentioning

confidence: 99%

Section: Synapse Formation and Functionmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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“…Mutations in PRICKLE1 disrupt its ability to increase the size of synaptic vesicles. Studies suggest that PRICKLE1 mutations contribute to ALB and seizures by disrupting the interaction with synapsin 1 and the regulation of synaptic vesicles, thus leading to abnormalities in the E/I ratio (Paemka et al 2013(Paemka et al , 2015.…”

Section: Genetics Of Epilepsy and Autismmentioning

confidence: 99%

Epilepsy and Autism

Buckley

Holmes

2016

Cold Spring Harb Perspect Med

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Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under-or overconnected or have a mixture of over-and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge.

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“…Indeed, we found that the postnatal deletion of Vangl2 initiated at P7 resulted in an increase in glutamatergic synapses, measured at P14. Because mutations of some PCP components, such as Prickle1 and Prickle2, have been implicated in autism and epilepsy, precisely pinpointing the function of PCP signaling components will lead to better understanding of the synaptopathy underlying many neurological and neuropsychiatric disorders (21)(22)(23)(24).…”

mentioning

confidence: 99%

Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

Thakar

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The signaling mechanisms that choreograph the assembly of the highly asymmetric pre-and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.Celsr3 | Vangl2 | glutamatergic | synapse formation G lutamatergic synapses, the predominant excitatory synapses in the brain, are asymmetric cell-cell junctions formed from distinct pre-and postsynaptic components involving highly organized complexes of hundreds of proteins across the 20-nm synaptic cleft (1, 2). The signaling pathway that directly assembles these asymmetric protein complexes has not been well understood. Understanding mechanisms of glutamatergic synapse formation will provide important insights into the function and plasticity as well as dysfunction of glutamatergic synapses, which underlie numerous nervous system disorders.Many epithelial tissues show planar cell polarity, the global asymmetry of cellular and tissue morphology and/or structure along the tissue plane (3, 4). The conserved core planar cell polarity (PCP) components, Frizzled, Dishevelled, Diego, Prickle, Vang(l), and Flamingo (Fmi)/Celsr, form asymmetric complexes at the cadherin-mediated adherens junctions that connect neighboring epithelial cells (3, 4). Recent studies suggest that mutations of some components of the PCP signaling pathway, Celsr3/Fmi and Vangl2, affect GABAergic circuit development in zebrafish retina, GABAergic motoneuron synapse development in Caenorhabditis elegans, and hippocampal/cortical glutamatergic and GABAergic synapse formation (5-11). PCP components are critical regulators of neuronal migration and axon guidance, which take p...

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PRICKLE1 Interaction with SYNAPSIN I Reveals a Role in Autism Spectrum Disorders

Cited by 41 publications

References 58 publications

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Epilepsy and Autism

Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

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