{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:01:29Z","timestamp":1772236889543,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,23]]},"group-title":"In Review","reference-count":138,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,4]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by ubiquitous SMN deficiency and loss of motor neurons. The persistence of motor and communication impairments, together with emerging cognitive and social deficits in severe Type I SMA patients treated early with SMN-restoring therapies, suggests a broader dysfunction involving neural circuits of the brain. To explore the potential supraspinal contributions to these emerging phenotypes, we investigated the cerebellum, a brain region critical for both motor and cognitive behaviors. Here, we identify cerebellar pathology in both\n                  <italic>post-mortem<\/italic>\n                  tissue from Type I SMA patients and a severe mouse model, which is characterized by lobule-specific Purkinje cell (PC) death driven by cell-autonomous, non-apoptotic p53-dependent mechanisms. Loss and dysfunction of excitatory parallel fiber synapses onto PC further contribute to cerebellar circuit disruption and altered PC firing. Furthermore, we identified impaired ultrasonic vocalization (USV) in a severe SMA mouse model\u2014a proxy for early-developing social communication skills that depend on cerebellar function. Cell-specific rescue experiments demonstrate that intrinsic cerebellar pathology contributes to motor and social communication impairments independently of spinal motor circuit abnormalities. Together, these findings establish cerebellar dysfunction as a pathogenic driver of neurodevelopmental motor and social defects, providing mechanistic insight into the persisting and emerging phenotypes of SMA.\n                <\/p>","DOI":"10.21203\/rs.3.rs-6819992\/v2","type":"posted-content","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T15:26:54Z","timestamp":1750692414000},"source":"Crossref","is-referenced-by-count":0,"title":["Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6529-1660","authenticated-orcid":false,"given":"Florian","family":"Gerstner","sequence":"first","affiliation":[{"name":"Carl-Ludwig-Institute for Physiology, Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Wittig","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Menedo","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayan","family":"Ruwald","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Carlini","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adela","family":"Vankova","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonie","family":"Sowoidnich","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerardo","family":"Martin-Lopez","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Dreilich","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Alonso-Collado","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Pagiazitis","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oumayma","family":"Aousji","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe","family":"Grzyb","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Smith","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1530-829X","authenticated-orcid":false,"given":"Mu","family":"Yang","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9935-6899","authenticated-orcid":false,"given":"Francesco","family":"Roselli","sequence":"additional","affiliation":[{"name":"Ulm University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Mentis","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5088-6012","authenticated-orcid":false,"given":"Charlotte","family":"Sumner","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-5628","authenticated-orcid":false,"given":"Livio","family":"Pellizzoni","sequence":"additional","affiliation":[{"name":"Columbia University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Simon","sequence":"additional","affiliation":[{"name":"Leipzig University"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.cell.2021.10.029","article-title":"D. 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J Clin Neurol 14:1\u20137. https:\/\/doi.org:10.3988\/jcn.2018.14.1.1","journal-title":"J Clin Neurol"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1093\/ijnp\/pyy043","article-title":"Motor Impairments Correlate with Social Deficits and Restricted Neuronal Loss in an Environmental Model of Autism","volume":"21","author":"Sagheer A","year":"2018","unstructured":"Sagheer A (2018) Motor Impairments Correlate with Social Deficits and Restricted Neuronal Loss in an Environmental Model of Autism. Int J Neuropsychopharmacol 21:871\u2013882. https:\/\/doi.org:10.1093\/ijnp\/pyy043","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.4103\/1673-5374.300340","article-title":"Ultrasonic vocalizations in mice: relevance for ethologic and neurodevelopmental disorders studies","volume":"16","author":"Premoli M","year":"2021","unstructured":"Premoli M, Memo M, Bonini SA (2021) Ultrasonic vocalizations in mice: relevance for ethologic and neurodevelopmental disorders studies. 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Hum Mol Genet 21:185\u2013195. https:\/\/doi.org:10.1093\/hmg\/ddr453","journal-title":"Hum Mol Genet"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1093\/hmg\/ddae190","article-title":"Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse","volume":"34","author":"Lee JC","year":"2025","unstructured":"Lee JC, Chung WK, Pisapia DJ, Henderson CE (2025) Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse. Hum Mol Genet 34:347\u2013367. https:\/\/doi.org:10.1093\/hmg\/ddae190","journal-title":"Hum Mol Genet"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13395-022-00305-9","article-title":"Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience","volume":"12","author":"Woschitz V","year":"2022","unstructured":"Woschitz V, Mei I, Hedlund E, Murray LM (2022) Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience. Skelet Muscle 12:22. https:\/\/doi.org:10.1186\/s13395-022-00305-9","journal-title":"Skelet Muscle"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"eade6992","DOI":"10.1126\/sciadv.ade6992","article-title":"Cortical circuits modulate mouse social vocalizations","volume":"9","author":"Gan-Or B","year":"2023","unstructured":"Gan-Or B, London M (2023) Cortical circuits modulate mouse social vocalizations. Sci Adv 9:eade6992. https:\/\/doi.org:10.1126\/sciadv.ade6992","journal-title":"Sci Adv"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ejpn.2024.05.002","article-title":"Cognitive function in SMA patients with 2 or 3 SMN2 copies treated with SMN-modifying or gene addition therapy during the first year of life","volume":"51","author":"Steffens P","year":"2024","unstructured":"Steffens P et al (2024) Cognitive function in SMA patients with 2 or 3 SMN2 copies treated with SMN-modifying or gene addition therapy during the first year of life. Eur J Paediatr Neurol 51:17\u201323. https:\/\/doi.org:10.1016\/j.ejpn.2024.05.002","journal-title":"Eur J Paediatr Neurol"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"4817","DOI":"10.1172\/JCI124120","article-title":"Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment","volume":"129","author":"Ramos DM","year":"2019","unstructured":"Ramos DM et al (2019) Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. J Clin Invest 129:4817\u20134831. https:\/\/doi.org:10.1172\/JCI124120","journal-title":"J Clin Invest"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"1270489","DOI":"10.3389\/fncel.2023.1270489","article-title":"Altered motor learning and coordination in mouse models of autism spectrum disorder","volume":"17","author":"Cording KR","year":"2023","unstructured":"Cording KR, Bateup HS (2023) Altered motor learning and coordination in mouse models of autism spectrum disorder. Front Cell Neurosci 17:1270489. https:\/\/doi.org:10.3389\/fncel.2023.1270489","journal-title":"Front Cell Neurosci"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.nmd.2011.09.007","article-title":"A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology","volume":"22","author":"Bowerman M","year":"2012","unstructured":"Bowerman M, Murray LM, Beauvais A, Pinheiro B, Kothary R (2012) A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul Disord 22:263\u2013276. https:\/\/doi.org:10.1016\/j.nmd.2011.09.007","journal-title":"Neuromuscul Disord"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation","volume":"264","author":"Gurney ME","year":"1994","unstructured":"Gurney ME et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772\u20131775. https:\/\/doi.org:10.1126\/science.8209258","journal-title":"Science"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/BF00293010","article-title":"Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration","volume":"6","author":"Cook SA","year":"1995","unstructured":"Cook SA, Johnson KR, Bronson RT, Davisson MT (1995) Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration. Mamm Genome 6:187\u2013191. https:\/\/doi.org:10.1007\/BF00293010","journal-title":"Mamm Genome"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1089\/hgtb.2017.192","article-title":"Protocol for Efficient Generation and Characterization of Adeno-Associated Viral Vectors","volume":"28","author":"Jungmann A","year":"2017","unstructured":"Jungmann A, Leuchs B, Rommelaere J, Katus HA, Muller OJ (2017) Protocol for Efficient Generation and Characterization of Adeno-Associated Viral Vectors. Hum Gene Ther Methods 28:235\u2013246. https:\/\/doi.org:10.1089\/hgtb.2017.192","journal-title":"Hum Gene Ther Methods"},{"key":"ref107","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36892","author":"Commisso B","year":"2018","unstructured":"Commisso B et al (2018) Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9. Elife 7 https:\/\/doi.org:10.7554\/eLife.36892"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"101236","DOI":"10.1016\/j.xpro.2022.101236","article-title":"Laser microscopy acquisition and analysis of premotor synapses in the murine spinal cord","volume":"3","author":"Buettner JM","year":"2022","unstructured":"Buettner JM, Kirmann T, Mentis GZ, Hallermann S, Simon CM (2022) Laser microscopy acquisition and analysis of premotor synapses in the murine spinal cord. STAR Protoc 3:101236. https:\/\/doi.org:10.1016\/j.xpro.2022.101236","journal-title":"STAR Protoc"},{"key":"ref109","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51771","article-title":"Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity","volume":"9","author":"Straub I","year":"2020","unstructured":"Straub I et al (2020) Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity. Elife 9. https:\/\/doi.org:10.7554\/eLife.51771","journal-title":"Elife"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.neuron.2014.08.036","article-title":"Ultrafast action potentials mediate kilohertz signaling at a central synapse","volume":"84","author":"Ritzau-Jost A","year":"2014","unstructured":"Ritzau-Jost A et al (2014) Ultrafast action potentials mediate kilohertz signaling at a central synapse. Neuron 84:152\u2013163. https:\/\/doi.org:10.1016\/j.neuron.2014.08.036","journal-title":"Neuron"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"2258","DOI":"10.1523\/JNEUROSCI.09-07-02258.1989","article-title":"Development of rat cerebellar Purkinje cells: electrophysiological properties following acute isolation and in long-term culture","volume":"9","author":"Hockberger PE","year":"1989","unstructured":"Hockberger PE, Tseng HY, Connor JA (1989) Development of rat cerebellar Purkinje cells: electrophysiological properties following acute isolation and in long-term culture. J Neurosci 9:2258\u20132271. https:\/\/doi.org:10.1523\/JNEUROSCI.09-07-02258.1989","journal-title":"J Neurosci"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1113\/jphysiol.2005.089383","article-title":"Physiological and morphological development of the rat cerebellar Purkinje cell","volume":"567","author":"McKay BE","year":"2005","unstructured":"McKay BE, Turner RW (2005) Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol 567:829\u2013850. https:\/\/doi.org:10.1113\/jphysiol.2005.089383","journal-title":"J Physiol"},{"key":"ref113","author":"Material","unstructured":"Material and Methods"},{"key":"ref114","author":"Study","unstructured":"Study design"},{"key":"ref115","unstructured":"Sample size and rules for stopping data collection were determined by previous experience and preliminary data All data was included if the experiment was technically sound (perfusion, tissue preparation, staining, recordings, imaging etc.). The endpoints for animals were selected by previous experiments and literature references. Each experiment was replicated at least three times in different animal\/autopsy tissue with the exception of p-p53 staining in human tissue due to its limited availability. The research objects were to investigate cerebellar pathology in mouse models for motor neuron diseases and autopsy tissue from SMA Type I patients. The mice were randomized to treatment group, and the investigators who assessed the behavioral, histological, USV and electrophysiological outcomes were blinded to the treatment groups"},{"key":"ref116","author":"Animal","unstructured":"Animal procedures"},{"key":"ref117","unstructured":"Breeding and experiments were performed in the animal facilities of Leipzig University Leipzig, Saxony, Germany and of Columbia University, New York, NY, USA. Animal procedures were performed according to European (Council Directive 86\/609\/EEC) and German (Tierschutzgesetz) guidelines for the welfare of experimental animals and the regional directorate (Landesdirektion) of Leipzig for Leipzig University, and according to National Institutes of Health Guidelines on the Care and Use of Animals and approved by the Columbia Animal Care and Use Committee (IACUC) for Columbia University"},{"key":"ref118","author":"Mice","unstructured":"Mice were housed in a 12h\/12h light\/dark cycle with access to food and water ad libitum. The following mouse lines were used: SMN\u22067 FVB (JAX stock #005025) 48, Smn2B\/\u2013 C57BL\/6 (Dr. Kothary) 103, SOD1-WT B6SJL (JAX stock #002297), SOD1-G93A B6SJL (JAX stock #002726) 104 and Ighmbp2NMD\u2009\u2013\u20092J C57BL\/6 (JAX stock #002521) 105. PVCre C57Bl\/6 (JAX stock #008069) and ChATCre C57Bl\/6 (JAX stock #006410) lines were crossed with SMN\u22067 mice to generate PvCre tg\/\u2013;Smn+\/\u2013;SMN2tg\/tg;SMN\u22067tg\/tg and ChatCretg\/\u2013;Smn+\/\u2013; SMN2tg\/tg;SMN\u22067tg\/tg mice. These strains were bred with mice expressing a Cre-inducible Smn allele (SMARes; JAX stock #007951) to generate SMARes+SMNChAT\u2013Cre, SMARes+SMNPV\u2013Cre or SMARes as previously described 21."},{"key":"ref119","unstructured":"The following primers were used for genotyping SMN\u22067: forward sequence (5\u2019 to 3\u2019)\u2009=\u2009GATGATTCTGACATTTGGGATG, reverse sequences (5\u2019 to 3\u2019)\u2009=\u2009TGGCTTATCTGGAGTTTCACAA and GAGTAACAACCCGTCGGATTC (wild-type band\u2009=\u2009325 base pairs (bp), mSmn KO\u2009=\u2009411 bp). Smn2B\/\u2013: forward sequence (5\u2019 to 3\u2019)\u2009=\u2009TTTGGCAGACTTTAGCAGGGC, reverse sequence (5\u2019 to 3\u2019)\u2009=\u2009AACTCCGGGTCCTCCTTCCT (wild-type band\u2009=\u2009500 bp, mutant\u2009=\u2009700 bp). SOD1-WT and SOD1-G93A: forward sequence (5\u2019 to 3\u2019)\u2009=\u2009CATCAGCCCTAATCCATCTGA, reverse sequence (5\u2019 to 3\u2019)\u2009=\u2009CGCGACTAACAATCAAAGTGA (transgene\u2009=\u2009236bp), Ighmbp2NMD\u2009\u2013\u20092J: forward sequence (5\u2019 to 3\u2019)\u2009=\u2009CTGGACAGAGAGAATACCTACAGACTGCTG, reverse sequence (5\u2019 to 3\u2019)\u2009=\u2009GTACTGCTCTGGCAGAAGACCCATGATTGC (wild-type\u2009=\u2009500 bp, mutant\u2009=\u2009300 bp). For genotyping of the SMARes+SMNChAT\u2013Cre, SMARes+SMNPV\u2013Cre mice, please see 21"},{"key":"ref120","volume-title":"9 gene delivery, P0 mice were anesthetized by isoflurane inhalation and injected in the right lateral ventricle of the brain with ~\u20091 x 1011 genome copies of AAV9 vectors in a PBS solution containing a vital dye","author":"For AAV","unstructured":"For AAV 9 gene delivery, P0 mice were anesthetized by isoflurane inhalation and injected in the right lateral ventricle of the brain with ~\u20091 x 1011 genome copies of AAV9 vectors in a PBS solution containing a vital dye (Fast Green; Sigma-Aldrich)"},{"key":"ref121","unstructured":"For phenotypic analysis SMN\u22067 mice treated with viral interventions were monitored daily for righting time, body weight, and posture time as previously reported 34. Each measurement was taken three times and averaged. To comply with animal welfare guidelines, mice that experienced a 25% weight loss in a single day and were unable to right themselves were euthanized. Righting time was defined as the time required for a pup to roll onto all four limbs after being placed on its back, maintaining this position for at least 3 seconds. Posture time measured how long a pup could sustain its balance while standing on all four limbs. The tests had a maximum duration of 60 seconds as indicated in the figure. Equal numbers of male and female mice were included, and data were combined, as no sex-specific differences were observed or have been previously reported in SMA"},{"key":"ref122","unstructured":"AAV9 vectors"},{"key":"ref123","unstructured":"The self-complementary AAV9-GFP AAV9-STAS and AAV9-p53shRNA vectors were previously described 18,19. For virus production, AAV-vectors were generated using a three plasmid standard protocol as previously reported 106,107 with pDGdeltaVP providing helper sequences, and a distinct rep-cap-helper plasmid with AAV9 wild-type capsid genes. Briefly, HEK293T cells were seeded in 15cm cell culture dishes and grown in DMEM\u2009+\u20091%Pen\/Strep\u2009+\u200910%FBS till 70% confluence, and then transfected with 2\u00b5gDNA\/1000bp using the PEI transfection reagent. Cells were harvested 3 days later, suspended in lysis buffer (50mM Tris-Cl, 150 mM NaCl, 5 mM MgClm with 2x Roche protease and phosphatase inhibitors cocktails added) and lysed by repeated freeze-thaw cycles; debris were cleared by centrifugation at 3000 x g for 10 min. The AAV fraction was purified from the raw cell lysate by layering on an Optiprep discontinuous gradient 60\/40\/20\/15% in PBS\u2009+\u2009Mg\/K and centrifuging at 350.000 x g 10\u00b0C for 90 min. The AAV fraction concentrated in the 40% Optiprep band was subject to de-salting in Zeba columns (Zeba Spin Desalting Columns, 10ml, 40.000 MWCO, Thermo 87772) further concentrated using centrifugal concentrators (Vivaspin 6, 100.000 MWCO Filter, GE Healthcare 28932319) at 4000 x g 4\u00b0C for 10 min, repeated till the full volume was concentrated. Viral titer was determined by qPCR with primers directed against ITR, as previously described 106"},{"key":"ref124","article-title":"The mCherry-Bcl-xL sequence under the control of the ubiquitous PGK promoter has been described previously 75","author":"The plasmid for the AAV9-Bcl","unstructured":"The plasmid for the AAV9-Bcl -xL was a kind gift from Robert Nickells. The mCherry-Bcl-xL sequence under the control of the ubiquitous PGK promoter has been described previously 75. The purified AAV9-Bcl-xL virus was produced by Vector Builder."},{"key":"ref125","article-title":"7-6-GFP are available from AddGene (Plasmid #126462) 76. The GFP was replaced by DNA fragments corresponding to the open reading frame of human SMN and packed into an AAV9 by Vector Builder","author":"The plasmid for the AAV9-L","unstructured":"The plasmid for the AAV9-L 7-6-GFP are available from AddGene (Plasmid #126462) 76. The GFP was replaced by DNA fragments corresponding to the open reading frame of human SMN and packed into an AAV9 by Vector Builder"},{"key":"ref126","unstructured":"Immunostaining of murine and human tissue"},{"key":"ref127","author":"Baltimore MD","unstructured":"For immunostaining of human cerebellar vermis, following parental- or patient-informed consent in strict observance of the legal and institutional ethical regulations, human tissues were collected at autopsy procedure at the Johns Hopkins University, Baltimore MD USA or was obtained from the NIH Neurobiobank at the University of Maryland, Baltimore, MD, USA (Supplementary Table 1). Human cerebellum tissue was cryoprotected with a 15% sucrose solution for at least 2 h until the tissue sank to the bottom of the tube. Afterwards, the tissue was transferred to a 30% sucrose solution and stored at 4\u00b0C overnight. The next day, the cerebellum tissue was embedded in Sakura Tissue Tek O.C.T. Compound and frozen in 2-Methylbutan cooled with liquid nitrogen. Tissues were cut at a Leica CM3050 S cryostat into 20 \u00b5m serial transverse sections at -20\u00b0C and subsequently stored at -80\u00b0C. Human cerebellar sections were incubated for 20 min in Polyscience L.A.B. solution for antigen retrieval at room temperature. Afterwards they were washed 3 times with PBS and blocked in 5% normal donkey serum in 0.3% PBS-T for 90 min. They were then incubated with the appropriate primary antibodies against PCP2 as PC marker and p-p53 (Supplementary Table 2) at 4\u00b0C overnight. The following day, after 6 washes of 10 min with PBS, 3 h incubation with secondary donkey antibodies coupled to Alexa488, Cy3 or Alexa647 (Jackson labs) diluted at 1:1000 in PBS-T were performed. After 6 times 10 min PBS washes, the slides were cover-slipped with glycerol:PBS (3:7) medium"},{"key":"ref128","unstructured":"For immunostaining of murine cerebellum and spinal cords, mice were perfused with PBS and 4% PFA following 4% PFA post-fixation overnight at 4\u00b0C On the following day, the brain and spinal cord were removed and washed in PBS. The cerebellum was then separated from the rest of the brain and split at the mid sagittal plane of the vermis. The hemispheres were removed, and half of the vermis was used for immunohistochemistry. The detailed protocol used for spinal cord dissection and identification of the lumbar L1 spinal segment has been previously reported 108. The vermis or L1 segment was then embedded in warm 5% agar and serial transverse sections (vermis\u2009=\u200970 \u00b5m, spinal cord\u2009=\u200975 \u00b5m) were cut at the vibratome (Leica VT1000S). The sections were blocked with 5% normal donkey serum in PBS with 0.3% Triton X-100 (PBS-T; pH 7.4) for 90 min. Then the primary antibodies in blocking solution (Supplementary Table 2) were added overnight at room temperature. The next day, after the sections were washed 6 times for 10 minutes in PBS-T, 3 h incubation with secondary donkey antibodies coupled to Alexa488, Cy3 or Alexa647 (Jackson labs) diluted at 1:1000 in PBS-T were performed. Subsequently the sections were washed 6 times for 10 min in PBS and were mounted on slides with glycerol:PBS (3:7) medium"},{"key":"ref129","unstructured":"For immunostaining of NMJs, mice were sacrificed or perfused and the muscle was dissected, immediately post-fixed with 4% PFA for 2 h and transferred into PBS The next day, single muscle fibers were teased and washed 3 times in PBS for 10 min each followed by staining of the postsynaptic part of the NMJ with a-bungarotoxin (BTX) labeled with Alexa Fluor 555 in PBS for 20 min. Subsequently, the muscle fibers were washed 5 times in PBS for 10 min and blocked with 5% donkey serum in PBS with 0.3% Triton X-100 (PBS-T) for 1 h. Mouse anti-Neurofilament (NF) and anti-Synaptic vesicle 2 (SV2) antibodies to immunolabel the presynaptic aspect of the NMJ were applied in blocking solution overnight at 4oC (Supplementary Table 2). The muscle fibers were then washed 3 times for 10 min in PBS. Secondary antibodies were applied for 1 h in PBS-T at room temperature. Finally, the muscle fibers were washed 3 times in PBS for 10 min and mounted on slides covered with glycerol:PBS (3:7) as previously described 24"},{"key":"ref130","author":"Confocal","unstructured":"Confocal imaging and analysis"},{"key":"ref131","author":"For PC","unstructured":"For PC quantification and lobule-specific analysis, 70 \u00b5m vermis sections were scanned using a 10x objective (NA\u2009=\u20090.40). A z-step size of 4.0 \u00b5m was chosen to include PCP2\u207a PC somata. Leica LAS X software automatically stitched individual horizontal image planes into a full image of each vermis section. Each stack was split into two smaller stacks (~\u200935 \u00b5m) for easier quantification of PCs and lobule sizes. The mean was calculated from each stack. Quantitative analysis of the vermis sections was done with Leica LAS AF software. The area of the entire vermis and individual lobules was measured using manual tracing. This method was also used to outline and quantify the molecular layer, PC layer, GC layer, and white matter for each of the 10 lobules. The perimeter of the PC layer was manually traced, and PCs were counted within each lobule. Three vermis sections per animal were analyzed"},{"key":"ref132","unstructured":"For all synaptic density scans, a segment of the molecular layer from a single lobule was selected, and images were taken using a 63x oil objective (NA\u2009=\u20091.30) for optimal magnification. A z-step size of 0.4 \u00b5m was used to capture detailed images of synapses on PC somata and dendrites. The z-compensation function adjusted laser intensity at each z-step to ensure balanced signal quality while avoiding sample damage. Two scans were performed per animal. Synaptic density on PCs was analyzed using Leica LAS X software. For each investigated lobule, a minimum 5 PCs were randomly selected for analysis of VGLUT1\u207a, VGLUT2\u207a, and VGAT\u207a synapses. Synapses were manually counted on the soma and on dendritic segments at two distances (0\u201350 \u00b5m and 50\u2013100 \u00b5m) from the soma. To minimize background-related errors, only synapses visible in at least two consecutive z-stack images were included"},{"key":"ref133","unstructured":"Intracellular recordings of Purkinje cells and granule cells in cerebellar sagittal slices"},{"key":"ref134","author":"Microm TF","unstructured":"Whole-cell patch-clamp recordings from PCs and GCs were performed as previously described 109,110 at P5 for PCs and P10 for both PCs and GCs. Following decapitation, the skull was opened, and the cerebellum was carefully extracted. Lateral portions of the cerebellum were trimmed to facilitate mounting in the vibratome chamber (HM 650 V, Microm TF, Scientific UK), which was filled with ice-cold (~\u20094\u00b0C), oxygenated (95% O\u2082 \/ 5% CO\u2082) sucrose-based artificial cerebrospinal fluid (aCSF) containing (in mM): 2.5 KCl, 1.1 CaCl\u2082, 4 MgCl\u2082, 25 NaHCO\u2083, 1.25 NaH\u2082PO\u2084\u00b7H\u2082O, 10 D-glucose, and 220 sucrose. Parasagittal cerebellar slices (300 \u00b5m thick) were prepared and transferred to a holding chamber containing standard aCSF, which was also used for recordings. This recording aCSF consisted of (in mM): 125 NaCl, 2.5 KCl, 1.25 NaH\u2082PO\u2084\u00b7H\u2082O, 26 NaHCO\u2083, 3 D-glucose, 1.1 CaCl\u2082\u00b7H\u2082O, 1 MgSO\u2084\u00b77H\u2082O, and 17 sucrose (310 mOsm, pH 7.3, equilibrated with carbogen). Slices were incubated at 35\u00b0C for 30 minutes, then maintained at room temperature (21\u201323\u00b0C) until use. For recordings, individual slices were transferred to a recording chamber and continuously perfused with oxygenated aCSF at room temperature. PCs were visually identified by their position in the PC layer and their large soma, as well as their distinctive morphology featuring a prominent, expansive dendritic tree extending into the molecular layer. GCs were also visually identified by their location in the GC layer and their small soma, along with a minimal dendritic arbor. Patch pipettes were pulled from borosilicate glass (GB200F-10, Science Products, Hofheim am Taunus) using a Flaming-Brown puller (P-97, Sutter Instruments, CA) to resistances of ~\u20094\u20137 M\u03a9 for PCs and ~\u20098\u201310 M\u03a9 for GCs. Pipettes were filled with an intracellular solution containing (in mM): 150 K-D-gluconate, 10 NaCl, 10 HEPES, 3 Mg-ATP, 0.3 Na-GTP, and 0.05 EGTA, adjusted to pH 7.3 with KOH and to an osmolarity of 290\u2013300 mOsm\/kg H\u2082O. Recordings were acquired in current-clamp or voltage-clamp mode using a HEKA EPC10\/2 amplifier (HEKA Elektronik, Lambrecht\/Pfalz, Germany) and digitized at 20 kHz with Patchmaster software (HEKA Elektronik). Signals were low-pass filtered at 3 kHz (DC\u20133 kHz; CyberAmp, Molecular Devices). RMP and spontaneous activity were recorded following a 10-second baseline with no current injection. Only cells with a RMP of \u2013\u200945 mV or lower, AP amplitudes of at least 30 mV, and the ability to repetitively fire 10 or more AP were included in further analysis as previously reported 111,112. Passive membrane properties were assessed in current-clamp mode by holding the cells at -80 mV membrane potential to inhibit spontaneous activity and injecting brief (300 ms) alternating current steps: 4 pA increments for PCs and 1 pA for GCs. Frequency-current (F\u2013I) relationships were determined by injecting 1-second depolarizing current steps (10 pA for PCs, 5 pA for GCs). Excitatory postsynaptic currents (EPSCs) were evoked by stimulation of parallel fibers for PCs or mossy fibers for GCs while holding the membrane potential at \u2013\u200970 mV. To isolate excitatory transmission during parallel fiber stimulation, 10 \u00b5M bicuculline was added to the bath solution to block GABAA receptor-mediated inhibition. The stimulation pipette, filled with recording aCSF, was positioned in the molecular layer for parallel fiber or granular layer for mossy fiber simulation. The stimulus intensity was adjusted to elicit EPSCs with amplitudes between 200\u2013600 pA to avoid action currents. Stimulation consisted of five pulses at 200 Hz for parallel fibers or 100 Hz for mossy fibers, with a duration of 200 \u00b5s per pulse. Data were analyzed offline using Patchmaster software (HEKA Elektronik)"},{"key":"ref135","unstructured":"USV analysis"},{"key":"ref136","unstructured":"USV experiments were performed at the Mouse NeuroBehavior Core of Columbia University To elicit USV emission, neonatal mouse pups were gently separated from the dam and placed in a small plastic container lined with a 0.5 cm layer of fresh bedding. The cage lid was immediately and gently placed back, to avoid agitating the dam and the remaining pups in the nest. The container with the isolated pup was immediately placed inside a sound-attenuating chamber (Med Associates) to minimize background noise and environmental disturbances. USVs were recorded using an ultrasound-sensitive microphone (Avisoft UltraSoundGate condenser microphone CM16, Avisoft Bioacoustics; frequency range: 10\u2013180 kHz) connected to a PC running Avisoft Recorder software. After each 3-minute recording session, the pup was marked to prevent repeated handling on the same day and returned to the nest. This procedure was repeated until all pups in the litter were tested. Recordings were performed on postnatal days P3, P5, P7 and P9. USV recordings were analyzed using Avisoft SASLab Pro software. Only frequencies above 35 kHz were analyzed. Spectrograms were generated using a Fast Fourier Transform (FFT) with a 512-length, frame size 100%, 50% overlap, and a Hamming window. Calls were manually labeled and parameters such as call number, duration, peak frequency, and inter-call interval were extracted for statistical analysis. In line with the Reduction principle of the 3Rs Guidelines in animal research, we minimized the number of animals used for USV analysis by reusing data from control and SMA mice across Fig. 4, Fig. 7, and Fig. S9. These groups were shared across experiments to reduce the overall number of animals without compromising scientific integrity. The AAV9-L7-6-SMN\u2013treated mutants were littermates of the other groups, and all recordings were performed concurrently"},{"key":"ref137","author":"Statistics","unstructured":"Statistics"},{"key":"ref138","unstructured":"In this manuscript, N refers to the number of patients or mice in each group, and n refers to the number of cells analyzed Results are presented as the mean\u2009\u00b1\u2009standard error (SE), based on at least three independent experiments involving three or more animals or patients per experimental group, unless specified otherwise in the figure legend. To assess the symmetry of data distribution, the Shapiro-Wilk normality test was applied. For comparisons between two groups, statistical analysis depended on the data's distribution and the equality of standard deviations (SDs). If the data followed a parametric distribution and the SDs were equal, an unpaired t-test or multiple t-test were used. When the SDs were unequal, Welch\u2019s t-test was applied. For nonparametric distributions, Mann-Whitney or multiple Mann-Whitney tests were performed. For comparisons among three groups or more, a one-way ANOVA followed by Tukey\u2019s multiple comparison test was used for parametric distributions. Nonparametric distributions were analyzed using the Kruskal-Wallis test with Dunn\u2019s correction. In cases where SDs were unequal, a Welch\u2019s ANOVA with Dunnett's T3 multiple comparison test was performed. For time-course comparisons involving more than two groups, a two-way ANOVA with Tukey\u2019s multiple comparison test was applied. The Log-rank (Mantel\u2013Cox) test was used for survival analysis. The statistical tests used for each experiment are indicated in the respective figure legends. All statistical analyses were conducted using GraphPad Prism 10, and p-values are reported within the figures"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-6819992\/v2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-6819992\/v2.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T15:27:12Z","timestamp":1750692432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-6819992\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":138,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-6819992\/v2","relation":{"is-version-of":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6819992\/v1","asserted-by":"subject"}],"has-version":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6819992\/v1","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2025,6,23]]},"subtype":"preprint"}}