Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity
<i>N</i>-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington’s disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR cu...
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MDPI AG
2022-09-01
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| author | Lígia Fão Patrícia Coelho Ricardo J. Rodrigues A. Cristina Rego |
| author_facet | Lígia Fão Patrícia Coelho Ricardo J. Rodrigues A. Cristina Rego |
| author_sort | Lígia Fão |
| collection | DOAJ |
| description | <i>N</i>-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington’s disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD. |
| first_indexed | 2024-03-09T21:54:07Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T21:54:07Z |
| publishDate | 2022-09-01 |
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| series | Cells |
| spelling | doaj.art-c343a3216f924d639654237c491520ba2023-11-23T20:02:03ZengMDPI AGCells2073-44092022-09-011119306310.3390/cells11193063Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB ActivityLígia Fão0Patrícia Coelho1Ricardo J. Rodrigues2A. Cristina Rego3Center for Neuroscience and Cell Biology (CNC), University of Coimbra (Pólo I), Rua Larga, 3004-504 Coimbra, PortugalCenter for Neuroscience and Cell Biology (CNC), University of Coimbra (Pólo I), Rua Larga, 3004-504 Coimbra, PortugalCenter for Neuroscience and Cell Biology (CNC), University of Coimbra (Pólo I), Rua Larga, 3004-504 Coimbra, PortugalCenter for Neuroscience and Cell Biology (CNC), University of Coimbra (Pólo I), Rua Larga, 3004-504 Coimbra, Portugal<i>N</i>-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington’s disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD.https://www.mdpi.com/2073-4409/11/19/3063fyn kinasemutant huntingtinNMDA receptorsHuntington’s diseaseCREBpost-synaptic density |
| spellingShingle | Lígia Fão Patrícia Coelho Ricardo J. Rodrigues A. Cristina Rego Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity Cells fyn kinase mutant huntingtin NMDA receptors Huntington’s disease CREB post-synaptic density |
| title | Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity |
| title_full | Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity |
| title_fullStr | Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity |
| title_full_unstemmed | Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity |
| title_short | Restored Fyn Levels in Huntington’s Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity |
| title_sort | restored fyn levels in huntington s disease contributes to enhanced synaptic glun2b composed nmda receptors and creb activity |
| topic | fyn kinase mutant huntingtin NMDA receptors Huntington’s disease CREB post-synaptic density |
| url | https://www.mdpi.com/2073-4409/11/19/3063 |
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