Editing AMPA receptor (section)

== AMPA Receptors in Disease Beyond Epilepsy ==
AMPA receptors are essential to excitatory neurotransmission in the CNS.<ref>{{Cite journal |last1=Traynelis |first1=Stephen F. |last2=Wollmuth |first2=Lonnie P. |last3=McBain |first3=Chris J. |last4=Menniti |first4=Frank S. |last5=Vance |first5=Katie M. |last6=Ogden |first6=Kevin K. |last7=Hansen |first7=Kasper B. |last8=Yuan |first8=Hongjie |last9=Myers |first9=Scott J. |last10=Dingledine |first10=Ray |date=September 2010 |title=Glutamate Receptor Ion Channels: Structure, Regulation, and Function |journal=Pharmacological Reviews |language=en |volume=62 |issue=3 |pages=405–496 |doi=10.1124/pr.109.002451 |pmc=2964903 |pmid=20716669}}</ref>  Beyond their established role in epilepsy, recent research indicates that AMPARs are implicated in various neurological and psychiatric disorders, including [[excitotoxicity]] in [[stroke]] and [[neurodegeneration]], as well as conditions like [[ALS|amyotrophic lateral sclerosis (ALS)]], [[Alzheimer's disease|Alzheimer's disease (AD)]], [[Huntington's disease]], [[schizophrenia]], and [[Autism spectrum disorders|autism spectrum disorders (ASD)]].<ref name=":7">{{Cite journal |last1=Wang |first1=Rui |last2=Reddy |first2=P. Hemachandra |date=2017-04-19 |title=Role of Glutamate and NMDA Receptors in Alzheimer's Disease |journal=Journal of Alzheimer's Disease |volume=57 |issue=4 |pages=1041–1048 |doi=10.3233/JAD-160763 |pmc=5791143 |pmid=27662322}}</ref><ref>{{Cite journal |last1=Fergani |first1=Anissa |last2=Dupuis |first2=Luc |last3=Jokic |first3=Natasa |last4=Larmet |first4=Yves |last5=de Tapia |first5=Marc |last6=Rene |first6=Frederique |last7=Loeffler |first7=Jean-Philippe |last8=Gonzalez de Aguilar |first8=Jose-Luis |date=2005 |title=Reticulons as Markers of Neurological Diseases: Focus on Amyotrophic Lateral Sclerosis |url=https://karger.com/NDD/article/doi/10.1159/000089624 |journal=Neurodegenerative Diseases |language=en |volume=2 |issue=3–4 |pages=185–194 |doi=10.1159/000089624 |pmid=16909024 |issn=1660-2854|url-access=subscription }}</ref><ref>{{Cite journal |last1=Shen |first1=Yong |last2=Tang |first2=Kejun |last3=Chen |first3=Dongdong |last4=Hong |first4=Mengying |last5=Sun |first5=Fangfang |last6=Wang |first6=SaiSai |last7=Ke |first7=Yuehai |last8=Wu |first8=Tingting |last9=Sun |first9=Ren |last10=Qian |first10=Jing |last11=Du |first11=Yushen |date=June 2021 |title=Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation |journal=Cell Reports |language=en |volume=35 |issue=12 |pages=109272 |doi=10.1016/j.celrep.2021.109272 |pmc=8363743 |pmid=34161773}}</ref><ref>{{Cite journal |last1=Talantova |first1=Maria |last2=Sanz-Blasco |first2=Sara |last3=Zhang |first3=Xiaofei |last4=Xia |first4=Peng |last5=Akhtar |first5=Mohd Waseem |last6=Okamoto |first6=Shu-ichi |last7=Dziewczapolski |first7=Gustavo |last8=Nakamura |first8=Tomohiro |last9=Cao |first9=Gang |last10=Pratt |first10=Alexander E. |last11=Kang |first11=Yeon-Joo |last12=Tu |first12=Shichun |last13=Molokanova |first13=Elena |last14=McKercher |first14=Scott R. |last15=Hires |first15=Samuel Andrew |date=2013-07-02 |title=Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss |journal=Proceedings of the National Academy of Sciences |language=en |volume=110 |issue=27 |pages=E2518-27 |doi=10.1073/pnas.1306832110 |doi-access=free |issn=0027-8424 |pmc=3704025 |pmid=23776240|bibcode=2013PNAS..110E2518T }}</ref><ref>{{Cite journal |last1=Fusar-Poli |first1=P. |last2=Radua |first2=J. |last3=McGuire |first3=P. |last4=Borgwardt |first4=S. |date=2012-11-01 |title=Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies |url=https://academic.oup.com/schizophreniabulletin/article-lookup/doi/10.1093/schbul/sbr134 |journal=Schizophrenia Bulletin |language=en |volume=38 |issue=6 |pages=1297–1307 |doi=10.1093/schbul/sbr134 |issn=0586-7614 |pmc=3494061 |pmid=22080494}}</ref><ref>{{Cite journal |last1=Gascoigne |first1=Karen E. |last2=Takeuchi |first2=Kozo |last3=Suzuki |first3=Aussie |last4=Hori |first4=Tetsuya |last5=Fukagawa |first5=Tatsuo |last6=Cheeseman |first6=Iain M. |date=April 2011 |title=Induced Ectopic Kinetochore Assembly Bypasses the Requirement for CENP-A Nucleosomes |journal=Cell |language=en |volume=145 |issue=3 |pages=410–422 |doi=10.1016/j.cell.2011.03.031 |pmc=3085131 |pmid=21529714}}</ref>

=== Excitotoxicity in Stroke and Neurodegeneration ===
Excessive activation of AMPARs, particularly those lacking the GluA2 subunit, leads to increased calcium permeability, contributing to neuronal injury and death—a phenomenon known as excitotoxity.  This mechanism in involved in acute events such as stroke and in chronic neurodegenerative diseases.<ref name=":7" /> For instance, in ALS, motor neurons exhibit elevated levels of calcium-permeable AMPARs, rendering them more susceptible to excitotoxic damage.<ref name=":8">{{Cite journal |last1=Lewerenz |first1=Jan |last2=Maher |first2=Pamela |date=2015-12-16 |title=Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? |journal=Frontiers in Neuroscience |volume=9 |page=469 |doi=10.3389/fnins.2015.00469 |doi-access=free |issn=1662-453X |pmc=4679930 |pmid=26733784}}</ref>

=== Role in ALS, Alzheimer's, and Huntington's Diseases ===

==== ALS ====
Motor neurons in ALS patients express high levels of calcium-permeable AMPARs, which, combined with reduced calcium-buffering capacity, make them vulnerable to excitotoxicity.<ref name=":8" />

==== Alzheimer's Disease ====
Alterations in AMPAR trafficking and function have been observed in Alzheimer's disease models.  Dysregulation of the Q/R editing site of the GluA2 subunit affects calcium permeability, influencing [[dendritic spine]] morphology and contributing to neurodegeneration and memory deficits.<ref>{{Cite journal |last1=Wright |first1=Amanda L. |last2=Konen |first2=Lyndsey M. |last3=Mockett |first3=Bruce G. |last4=Morris |first4=Gary P. |last5=Singh |first5=Anurag |last6=Burbano |first6=Lisseth Estefania |last7=Milham |first7=Luke |last8=Hoang |first8=Monica |last9=Zinn |first9=Raphael |last10=Chesworth |first10=Rose |last11=Tan |first11=Richard P. |last12=Royle |first12=Gordon A. |last13=Clark |first13=Ian |last14=Petrou |first14=Steven |last15=Abraham |first15=Wickliffe C. |date=2023-09-28 |title=The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer's disease |journal=Molecular Neurodegeneration |language=en |volume=18 |issue=1 |page=65 |doi=10.1186/s13024-023-00632-5 |doi-access=free |issn=1750-1326 |pmc=10537207 |pmid=37759260}}</ref>

==== Huntington's Disease ====
Mutant [[Huntingtin|huntingtin protein]] disrupts AMPAR-mediated synaptic transmission by impairing receptor trafficking, leading to synaptic dysfunction and neuronal loss in Huntington's disease models.<ref>{{Cite journal |last1=Mandal |first1=Madhuchhanda |last2=Wei |first2=Jing |last3=Zhong |first3=Ping |last4=Cheng |first4=Jia |last5=Duffney |first5=Lara J. |last6=Liu |first6=Wenhua |last7=Yuen |first7=Eunice Y. |last8=Twelvetrees |first8=Alison E. |last9=Li |first9=Shihua |last10=Li |first10=Xiao-Jiang |last11=Kittler |first11=Josef T. |last12=Yan |first12=Zhen |date=September 2011 |title=Impaired α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Trafficking and Function by Mutant Huntingtin |journal=Journal of Biological Chemistry |language=en |volume=286 |issue=39 |pages=33719–33728 |doi=10.1074/jbc.M111.236521 |doi-access=free |pmc=3190808 |pmid=21832090}}</ref>

=== AMPAR Trafficking Deficits in Schizophrenia and Autism ===

==== Schizophrenia ====
Abnormal [[N-linked glycosylation]] of AMPAR subunits has been reported in schizophrenia, suggesting impaired receptor trafficking and synaptic localization, which may underlie [[glutamatergic]] dysfunction observed in the disorder.<ref>{{Cite journal |last1=Tucholski |first1=Janusz |last2=Simmons |first2=Micah S. |last3=Pinner |first3=Anita L. |last4=Haroutunian |first4=Vahram |last5=McCullumsmith |first5=Robert E. |last6=Meador-Woodruff |first6=James H. |date=May 2013 |title=Abnormal N-linked glycosylation of cortical AMPA receptor subunits in schizophrenia |journal=Schizophrenia Research |language=en |volume=146 |issue=1–3 |pages=177–183 |doi=10.1016/j.schres.2013.01.031 |pmc=3655690 |pmid=23462048}}</ref>

==== Autism Spectrum Disorders (ASD) ====
Alterations in AMPAR trafficking have been implicated in ASD.  Studies indicate that dysregulation of proteins involved in AMPAR trafficking, such as [[CYFIP1]], leads to synaptic dysfunction associated with autism-like behaviors.<ref>{{Cite journal |last1=Pathania |first1=M |last2=Davenport |first2=E C |last3=Muir |first3=J |last4=Sheehan |first4=D F |last5=López-Doménech |first5=G |last6=Kittler |first6=J T |date=2014-03-25 |title=The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines |journal=Translational Psychiatry |language=en |volume=4 |issue=3 |pages=e374 |doi=10.1038/tp.2014.16 |issn=2158-3188 |pmc=3966042 |pmid=24667445}}</ref>