{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:20:10Z","timestamp":1792153210006,"version":"4.4.0"},"posted":{"date-parts":[[2024,7,24]]},"group-title":"Neuroscience","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected \u03b1-synuclein (\u03b1Syn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed \u03b1Syn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that \u03b1Syn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of \u03b1Syn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of \u03b1Syn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with \u03b1Syn pathology. Our results documented motor cortical neuronal hyperexcitability associated with \u03b1Syn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.<\/jats:p>","DOI":"10.1101\/2024.07.24.604995","type":"posted-content","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T02:55:10Z","timestamp":1721876110000},"source":"Crossref","is-referenced-by-count":2,"title":["Motor Cortical Neuronal Hyperexcitability Associated with \u03b1-Synuclein Aggregation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-1129","authenticated-orcid":false,"given":"Liqiang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-7900","authenticated-orcid":false,"given":"Hiba Douja","family":"Chehade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-683X","authenticated-orcid":false,"given":"Hong-Yuan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024081704150611000_2024.07.24.604995v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28538"},{"key":"2024081704150611000_2024.07.24.604995v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(89)90074-X"},{"key":"2024081704150611000_2024.07.24.604995v2.3","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.neuron.2016.02.001","article-title":"Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning","volume":"89","year":"2016","journal-title":"Neuron"},{"key":"2024081704150611000_2024.07.24.604995v2.4","doi-asserted-by":"crossref","first-page":"fcab273","DOI":"10.1093\/braincomms\/fcab273","article-title":"Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo","volume":"3","year":"2021","journal-title":"Brain Commun"},{"key":"2024081704150611000_2024.07.24.604995v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"2024081704150611000_2024.07.24.604995v2.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124593"},{"key":"2024081704150611000_2024.07.24.604995v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.08.007"},{"key":"2024081704150611000_2024.07.24.604995v2.8","doi-asserted-by":"crossref","first-page":"100786","DOI":"10.1016\/j.xpro.2021.100786","article-title":"Intraspinal injection of adeno-associated viruses into the adult mouse spinal cord","volume":"2","year":"2021","journal-title":"Star Protoc"},{"key":"2024081704150611000_2024.07.24.604995v2.9","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2694-20.2021"},{"key":"2024081704150611000_2024.07.24.604995v2.10","doi-asserted-by":"crossref","first-page":"eadg3038","DOI":"10.1126\/sciadv.adg3038","article-title":"Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism","volume":"9","year":"2023","journal-title":"Sci Adv"},{"key":"2024081704150611000_2024.07.24.604995v2.11","doi-asserted-by":"crossref","unstructured":"Chen L , Nagaraja C , Daniels S , Fisk ZA , Dvorak R , Meyerdirk L , Steiner JA , Galvis MLE , Henderson MX , Rousseaux MWC , Brundin P , Chu H-Y (2022) Synaptic location is a determinant of the detrimental effects of \u03b1-Synuclein pathology to glutamatergic transmission in the basolateral amygdala. 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