{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:47:58Z","timestamp":1792140478508,"version":"4.4.0"},"reference-count":89,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The cortical motor network excitatory-inhibitory (E\/I) imbalance contributes to several neurodegenerative movement disorders. Spinal Muscular Atrophy (SMA) is a neuromuscular disease due to the lack of Survival Motor Neuron (SMN) protein, characterized by lower motor neuron (MN) degeneration and muscle atrophy. However, evidence shows that SMA patients display motor cortex abnormalities correlating with disease severity, suggesting altered maturation and maladaptive plasticity potentially contributing to upper MN vulnerability. This raises questions about cortical involvement and highlights the need for preclinical studies to clarify underlying mechanisms, given the limited accessibility of early-stage, untreated brain tissue from SMA patients. In agreement, our previous work in SMA mice revealed upper MN vulnerability, indicating SMA pathogenesis is far more complex than classically conceived. Here, by employing a combination of imaging, molecular techniques, and electrophysiological characterization of cortical inhibitory neurotransmission, we dissected GABAergic signalling, metabolism, and interneuron function in the sensorimotor cortex and primary neuron-astrocyte co-cultures of a severe SMA mouse model. Additionally, we conducted bioinformatic analyses and biochemical assays to assess age-dependent modulation of neurotransmitter pathways and quantify key metabolites across different stages of the disease, with the overall aim of evaluating correlations between GABA levels, its precursor glutamine, the expression of synthetic enzymes (GAD65\/67), and the density of Parvalbumin-positive interneurons with SMN deficiency. We unveiled a significant association between SMN deficiency and impaired density, morphology and signalling of GABAergic Parvalbumin positive interneurons in the sensorimotor cortex of late-stage SMA mice, suggesting E\/I imbalance and possibly contributing to shape upper MN vulnerability. We also highlighted the pivotal role of SMN, as involved in pre-mRNA splicing, in its impact on neuronal-astrocyte interactions regulating GABA metabolism, release and reuptake. These findings underscore a role for altered motor cortical GABAergic neurotransmission in SMA progression and offer a new key perspective to achieving novel, comprehensive therapeutic approaches.<\/jats:p>","DOI":"10.1038\/s41419-026-08520-8","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T06:21:44Z","timestamp":1772259704000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Changes in the cortical GABAergic inhibitory system in a Spinal Muscular Atrophy mouse model"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1141-329X","authenticated-orcid":false,"given":"Giovanna","family":"Menduti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4779-005X","authenticated-orcid":false,"given":"Francesco","family":"Ferrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Caretto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-3517","authenticated-orcid":false,"given":"Raffaella","family":"di Vito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4246-8863","authenticated-orcid":false,"given":"Giada","family":"Beltrando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Marnetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-6357","authenticated-orcid":false,"given":"Ferdinando","family":"Di Cunto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Boido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5909-2128","authenticated-orcid":false,"given":"Alessandro","family":"Vercelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"8520_CR1","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1146\/annurev-pharmtox-032320-015420","volume":"61","author":"S Ghatak","year":"2021","unstructured":"Ghatak S, Talantova M, McKercher SR, Lipton SA. Novel therapeutic approach for excitatory\/inhibitory imbalance in neurodevelopmental and neurodegenerative diseases. Annu Rev Pharm Toxicol. 2021;61:701\u201321.","journal-title":"Annu Rev Pharm Toxicol"},{"key":"8520_CR2","doi-asserted-by":"crossref","unstructured":"Taube W, Lauber B. Changes in the cortical GABAergic inhibitory system with ageing and ageing-related neurodegenerative diseases. J Physiol. 2024;604:689\u2013706.","DOI":"10.1113\/JP285656"},{"key":"8520_CR3","doi-asserted-by":"crossref","unstructured":"Alharbi B, Al-kuraishy HM, Al-Gareeb AI, Elekhnawy E, Alharbi H, Alexiou A, et al. Role of GABA pathway in motor and non-motor symptoms in Parkinson\u2019s disease: a bidirectional circuit. Eur J Med Res. 2024;29:205.","DOI":"10.1186\/s40001-024-01779-7"},{"key":"8520_CR4","doi-asserted-by":"crossref","unstructured":"Pressl C, M\u00e4tlik K, Kus L, Darnell P, Luo JD, Paul MR, et al. Selective vulnerability of layer 5a corticostriatal neurons in Huntington\u2019s disease. Neuron. 2024;112:924\u2013941.e10.","DOI":"10.1016\/j.neuron.2023.12.009"},{"key":"8520_CR5","doi-asserted-by":"crossref","unstructured":"Pradhan J, Bellingham MC. Neurophysiological mechanisms underlying cortical hyper-excitability in amyotrophic lateral sclerosis: a review. Brain Sci. 2021;11:549.","DOI":"10.3390\/brainsci11050549"},{"key":"8520_CR6","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1212\/WNL.0b013e3182563b57","volume":"78","author":"BR Foerster","year":"2012","unstructured":"Foerster BR, Callaghan BC, Petrou M, Edden RAE, Chenevert TL, Feldman EL. Decreased motor cortex \u03b3-aminobutyric acid in amyotrophic lateral sclerosis. Neurology. 2012;78:1596\u2013600.","journal-title":"Neurology"},{"key":"8520_CR7","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","volume":"80","author":"S Lefebvre","year":"1995","unstructured":"Lefebvre S, B\u00fcrglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155\u201365.","journal-title":"Cell"},{"key":"8520_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2018.00017","volume":"12","author":"M Boido","year":"2018","unstructured":"Boido M, de Amicis E, Valsecchi V, Trevisan M, Ala U, Ruegg MA, et al. Increasing agrin function antagonizes muscle atrophy and motor impairment in spinal muscular atrophy. Front Cell Neurosci. 2018;12:1\u201314.","journal-title":"Front Cell Neurosci"},{"key":"8520_CR9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/joa.12083","volume":"224","author":"M Shababi","year":"2014","unstructured":"Shababi M, Lorson CL, Rudnik-Sch\u00f6neborn SS. Spinal muscular atrophy: A motor neuron disorder or a multi-organ disease?. J Anat. 2014;224:15\u201328.","journal-title":"J Anat"},{"key":"8520_CR10","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.neuroscience.2020.10.038","volume":"452","author":"A Tharaneetharan","year":"2021","unstructured":"Tharaneetharan A, Cole M, Norman B, Romero NC, Wooltorton JRA, Harrington MA, et al. Functional abnormalities of cerebellum and motor cortex in spinal muscular atrophy mice. Neuroscience. 2021;452:78\u201397.","journal-title":"Neuroscience"},{"key":"8520_CR11","doi-asserted-by":"crossref","unstructured":"Mugisha N, Oliveira-Carneiro A, Behlim T, Oskoui M. Brain Magnetic Resonance Imaging (MRI) in Spinal Muscular Atrophy: A Scoping Review. J Neuromuscul Dis. 2023;10:493\u2013503.","DOI":"10.3233\/JND-221567"},{"key":"8520_CR12","doi-asserted-by":"crossref","unstructured":"Harding BN, Kariya S, Monani UR, Chung WK, Benton M, Yum SW, et al. Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I. J Neuropathol Exp Neurol. 2015;74:15\u201324.","DOI":"10.1097\/NEN.0000000000000144"},{"key":"8520_CR13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1001\/archneurol.2011.1697","volume":"69","author":"MA Farrar","year":"2012","unstructured":"Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and adaptation in spinal muscular atrophy. Arch Neurol. 2012;69:467\u201373.","journal-title":"Arch Neurol"},{"key":"8520_CR14","doi-asserted-by":"crossref","unstructured":"Coffey A, Bista S, Mitchell M, Giglia R, Carson R, Lowery M, et al. Cortico-Muscular Coherence Patterns in Spinal Muscular Atrophy (2318). Neurology. 2020;94(Suppl 15):2318.","DOI":"10.1212\/WNL.94.15_supplement.2318"},{"key":"8520_CR15","doi-asserted-by":"crossref","unstructured":"Querin G, El Mendili MM, Lenglet T, Behin A, Stojkovic T, Salachas F, et al. The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study. NeuroImage Clin. 2019;21:101618.","DOI":"10.1016\/j.nicl.2018.101618"},{"key":"8520_CR16","doi-asserted-by":"crossref","unstructured":"Stam M, Tan HHG, Schmidt R, van den Heuvel MP, van den Berg LH, Wadman RI, et al. Brain magnetic resonance imaging of patients with spinal muscular atrophy type 2 and 3. NeuroImage Clin. 2024;44:103708.","DOI":"10.1016\/j.nicl.2024.103708"},{"key":"8520_CR17","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00401-003-0743-9","volume":"106","author":"S Araki","year":"2003","unstructured":"Araki S, Hayashi M, Tamagawa K, Saito M, Kato S, Komori T, et al. Neuropathological analysis in spinal muscular atrophy type II. Acta Neuropathol. 2003;106:441\u20138.","journal-title":"Acta Neuropathol"},{"key":"8520_CR18","doi-asserted-by":"publisher","first-page":"4216","DOI":"10.1093\/hmg\/ddq340","volume":"19","author":"TM Wishart","year":"2010","unstructured":"Wishart TM, Huang JPW, Murray LM, Lamont DJ, Mutsaers CA, Ross J, et al. SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. 2010;19:4216\u201328.","journal-title":"Hum Mol Genet"},{"key":"8520_CR19","doi-asserted-by":"crossref","unstructured":"D\u2019Errico P, Boido M, Piras A, Valsecchi V, De Amicis E, Locatelli D, et al. Selective vulnerability of spinal and cortical motor neuron subpopulations in delta7 SMA mice. PLoS One. 2013;8:e82654.","DOI":"10.1371\/journal.pone.0082654"},{"key":"8520_CR20","doi-asserted-by":"crossref","unstructured":"Menduti G, Ras\u00e0 DM, Stanga S, Boido M Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment. Front Pharmacol. 2020;11:592234.","DOI":"10.3389\/fphar.2020.592234"},{"key":"8520_CR21","doi-asserted-by":"publisher","unstructured":"Hatanaka F, Suzuki K, Shojima K, Yu J, Takahashi Y, Sakamoto A, et al. Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing. Nat Commun. 2024. https:\/\/doi.org\/10.1038\/s41467-024-50095-5.","DOI":"10.1038\/s41467-024-50095-5"},{"key":"8520_CR22","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1002\/jcsm.13486","volume":"15","author":"J Rhee","year":"2024","unstructured":"Rhee J, Kang JS, Jo YW, Yoo K, Kim YL, Hann SH, et al. Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant. J Cachexia Sarcopenia Muscle. 2024;15:1404\u201317.","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"8520_CR23","doi-asserted-by":"publisher","unstructured":"Wadman RI, van der Pol WL, Bosboom WMJ, Asselman FL, van den Berg LH, Iannaccone ST, et al. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev. 2020;CD006282. https:\/\/doi.org\/10.1002\/14651858.CD006282.pub5.","DOI":"10.1002\/14651858.CD006282.pub5"},{"key":"8520_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0021296","volume":"6","author":"JT Kissel","year":"2011","unstructured":"Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, et al. SMA CARNI-VAL TRIAL PART II: A prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011;6:1\u201311.","journal-title":"PLoS One"},{"key":"8520_CR25","doi-asserted-by":"crossref","unstructured":"Nascimento OJM, Orsini M, Quintanilha G. Lamotrigine on motor symptoms of spinal muscular atrophies. Rev Neurol. 2010;50:127\u20138.","DOI":"10.33588\/rn.5002.2009267"},{"key":"8520_CR26","doi-asserted-by":"crossref","unstructured":"Dimitriadi M, Kye MJ, Kalloo G, Yersak JM, Sahin M, Hart AC. The Neuroprotective Drug Riluzole Acts via Small Conductance Ca2+-Activated K+ Channels to Ameliorate Defects in Spinal Muscular Atrophy Models. J Neurosci. 2013;33:6557\u201362.","DOI":"10.1523\/JNEUROSCI.1536-12.2013"},{"key":"8520_CR27","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1177\/08830738030180080501","volume":"18","author":"L Merlini","year":"2003","unstructured":"Merlini L, Solari A, Vita G, Bertini E, Minetti C, Mongini T, et al. Role of Gabapentin in Spinal Muscular Atrophy. J Child Neurol. 2003;18:537\u201341.","journal-title":"J Child Neurol"},{"key":"8520_CR28","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1093\/hmg\/ddq459","volume":"20","author":"JN Sleigh","year":"2011","unstructured":"Sleigh JN, Buckingham SD, Esmaeili B, Viswanathan M, Cuppen E, Westlund BM, et al. A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds. Hum Mol Genet. 2011;20:245\u201360.","journal-title":"Hum Mol Genet"},{"key":"8520_CR29","doi-asserted-by":"crossref","unstructured":"Ando S, Funato M, Ohuchi K, Inagaki S, Sato A, Seki J, et al. The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular Atrophy Model. Neurochem Res. 2019;44:1773\u20139.","DOI":"10.1007\/s11064-019-02814-4"},{"key":"8520_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2020.107966","volume":"168","author":"GJ Sills","year":"2020","unstructured":"Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacol. 2020;168:107966.","journal-title":"Neuropharmacol"},{"key":"8520_CR31","doi-asserted-by":"crossref","unstructured":"Foga\u00e7a MV, Duman RS Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci. 2019;13:87.","DOI":"10.3389\/fncel.2019.00087"},{"key":"8520_CR32","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1152\/jn.00652.2018","volume":"122","author":"KA Quinlan","year":"2019","unstructured":"Quinlan KA, Reedich EJ, Arnold WD, Puritz AC, Cavarsan CF, Heckman CJ, et al. Hyperexcitability precedes motoneuron loss in the Smn2B\/- mouse model of spinal muscular atrophy. J Neurophysiol. 2019;122:1297\u2013311.","journal-title":"J Neurophysiol"},{"key":"8520_CR33","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.neuron.2010.12.032","volume":"69","author":"GZ Mentis","year":"2011","unstructured":"Mentis GZ, Blivis D, Liu W, Drobac E, Crowder ME, Kong L, et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron. 2011;69:453\u201367.","journal-title":"Neuron"},{"key":"8520_CR34","doi-asserted-by":"crossref","unstructured":"Sun J, Harrington MA. The alteration of intrinsic excitability and synaptic transmission in lumbar spinal motor neurons and interneurons of severe spinal muscular atrophy mice. Front Cell Neurosci. 2019;13:15.","DOI":"10.3389\/fncel.2019.00015"},{"key":"8520_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adt4126","volume":"11","author":"EV Fletcher","year":"2025","unstructured":"Fletcher EV, Chalif JI, Rotterman TM, Pagiazitis JG, Van Alstyne M, Sivakumar N, et al. Synaptic imbalance and increased inhibition impair motor function in SMA. Sci Adv. 2025;11:eadt4126.","journal-title":"Sci Adv"},{"key":"8520_CR36","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/hmg\/ddi078","volume":"14","author":"TT Le","year":"2005","unstructured":"Le TT, Pham LT, Butchbach MER, Zhang HL, Monani UR, Coovert DD, et al. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet. 2005;14:845\u201357.","journal-title":"Hum Mol Genet"},{"key":"8520_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0128560","volume":"10","author":"V Valsecchi","year":"2015","unstructured":"Valsecchi V, Boido M, De Amicis E, Piras A, Vercelli A. Expression of muscle-specific MiRNA 206 in the progression of disease in a murine SMA model. PLoS One. 2015;10:1\u201317.","journal-title":"PLoS One"},{"key":"8520_CR38","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1038\/s41419-017-0086-4","volume":"8","author":"A Piras","year":"2017","unstructured":"Piras A, Schiaffino L, Boido M, Valsecchi V, Guglielmotto M, De Amicis E, et al. Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy. Cell Death Dis. 2017;8:3223.","journal-title":"Cell Death Dis"},{"key":"8520_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnmol.2018.00308","volume":"11","author":"R Schellino","year":"2018","unstructured":"Schellino R, Boido M, Borsello T, Vercelli A. Pharmacological c-Jun NH2-Terminal Kinase (JNK) pathway inhibition reduces severity of spinal muscular atrophy disease in mice. Front Mol Neurosci. 2018;11:1\u201315.","journal-title":"Front Mol Neurosci"},{"key":"8520_CR40","doi-asserted-by":"crossref","unstructured":"Hertz L The Glutamate\u2013Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation. Front Endocrinol. 2013;4:59.","DOI":"10.3389\/fendo.2013.00059"},{"key":"8520_CR41","doi-asserted-by":"crossref","unstructured":"Lazarus MS, Krishnan K, Huang ZJ. GAD67 Deficiency in Parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex. Cereb Cortex. 2015:1290\u20136.","DOI":"10.1093\/cercor\/bht322"},{"key":"8520_CR42","doi-asserted-by":"crossref","unstructured":"Chattopadhyaya B, Cristo G Di, Wu CZ, Knott G, Kuhlman S, et al. Article GAD67-Mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron. 2007;54:889\u2013903.","DOI":"10.1016\/j.neuron.2007.05.015"},{"key":"8520_CR43","doi-asserted-by":"crossref","unstructured":"Uchida T, Furukawa T, Iwata S, Yanagawa Y, Fukuda A. Selective loss of parvalbumin-positive GABAergic interneurons in the cerebral cortex of maternally stressed Gad1 -heterozygous mouse offspring. Transl Psychiatry. 2014:1\u201310.","DOI":"10.1038\/tp.2014.13"},{"key":"8520_CR44","doi-asserted-by":"crossref","unstructured":"Bolneo E, Chau PYS, Noakes PG. Investigating the role of GABA in neural development and disease using mice lacking GAD67 or VGAT genes. Int J Mol Sci. 2022;23:7965.","DOI":"10.3390\/ijms23147965"},{"key":"8520_CR45","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1152\/physrev.00017.2006","volume":"87","author":"Y Ben-Ari","year":"2007","unstructured":"Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215\u201384.","journal-title":"Physiol Rev"},{"key":"8520_CR46","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1113\/jphysiol.2004.077495","volume":"562","author":"C Rivera","year":"2005","unstructured":"Rivera C, Voipio J, Kaila K. Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol. 2005;562:27\u201336.","journal-title":"J Physiol"},{"key":"8520_CR47","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nrn3819","volume":"15","author":"K Kaila","year":"2014","unstructured":"Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15:637\u201354.","journal-title":"Nat Rev Neurosci"},{"key":"8520_CR48","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S0092-8674(01)00341-5","volume":"105","author":"K Ganguly","year":"2001","unstructured":"Ganguly K, Schinder AF, Wong ST, Poo M.GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell. 2001;105:521\u201332.","journal-title":"Cell"},{"key":"8520_CR49","doi-asserted-by":"publisher","first-page":"5224","DOI":"10.1523\/JNEUROSCI.5169-06.2007","volume":"27","author":"L Cancedda","year":"2007","unstructured":"Cancedda L, Fiumelli H, Chen K, Poo M. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci J Soc Neurosci. 2007;27:5224\u201335.","journal-title":"J Neurosci J Soc Neurosci"},{"key":"8520_CR50","doi-asserted-by":"crossref","unstructured":"Park C, Chen X, Tian CL, Park GN, Chenouard N, Lee H, et al. Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking. Proc Natl Acad Sci USA. 2021;118:e2022133118.","DOI":"10.1073\/pnas.2022133118"},{"key":"8520_CR51","doi-asserted-by":"crossref","unstructured":"Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698\u2013702.","DOI":"10.1038\/nature07991"},{"key":"8520_CR52","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nature08002","volume":"459","author":"JA Cardin","year":"2009","unstructured":"Cardin JA, Carl\u00e9n M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663\u20137.","journal-title":"Nature"},{"key":"8520_CR53","doi-asserted-by":"crossref","unstructured":"David F, Borel M, Ayub S, Ruther P, Gentet LJ. Layer-specific stimulations of parvalbumin-positive cortical interneurons in mice entrain brain rhythms to different frequencies. Cereb Cortex. 2023;33:8286\u201399.","DOI":"10.1093\/cercor\/bhad114"},{"key":"8520_CR54","doi-asserted-by":"crossref","unstructured":"Petkova-Tuffy A, G\u00f6decke N, Viotti J, Korte M, Dresbach T. Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling. BMC Biol. 2021;19:215.","DOI":"10.1186\/s12915-021-01145-7"},{"key":"8520_CR55","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/j.celrep.2017.10.010","volume":"21","author":"P Bernab\u00f2","year":"2017","unstructured":"Bernab\u00f2 P, Tebaldi T, Groen EJN, Lane FM, Perenthaler E, Mattedi F, et al. In vivo translatome profiling in spinal muscular atrophy reveals a role for SMN protein in ribosome biology. Cell Rep. 2017;21:953\u201365.","journal-title":"Cell Rep"},{"key":"8520_CR56","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.cell.2008.03.031","volume":"133","author":"Z Zhang","year":"2008","unstructured":"Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M, et al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell. 2008;133:585\u2013600.","journal-title":"Cell"},{"key":"8520_CR57","doi-asserted-by":"crossref","unstructured":"Servais L, Baranello G, Scoto M, Daron A, Oskoui M. Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities. Expert Opin Investig Drugs. 2021;30:519\u201327.","DOI":"10.1080\/13543784.2021.1904889"},{"key":"8520_CR58","doi-asserted-by":"publisher","first-page":"241","DOI":"10.3389\/fncel.2014.00241","volume":"8","author":"R Tapia","year":"2014","unstructured":"Tapia R. Cellular and molecular mechanisms of motor neuron death in amyotrophic lateral sclerosis: a perspective. Front Cell Neurosci. 2014;8:241.","journal-title":"Front Cell Neurosci"},{"key":"8520_CR59","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1111\/j.1460-9568.2010.07158.x","volume":"31","author":"G Spigolon","year":"2010","unstructured":"Spigolon G, Veronesi C, Bonny C, Vercelli A. c-Jun N-terminal kinase signaling pathway in excitotoxic cell death following kainic acid-induced status epilepticus. Eur J Neurosci. 2010;31:1261\u201372.","journal-title":"Eur J Neurosci"},{"key":"8520_CR60","doi-asserted-by":"crossref","unstructured":"Menduti G, Vitaliti A, Capo CR, Lettieri-Barbato D, Aquilano K, Malaspina P, et al. SSADH Variants increase susceptibility of U87 cells to mitochondrial pro-oxidant insult. Int J Mol Sci. 2020;21:4374.","DOI":"10.3390\/ijms21124374"},{"key":"8520_CR61","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.3390\/ijms18081813","volume":"18","author":"K Govindpani","year":"2017","unstructured":"Govindpani K, Guzm\u00e1n BCF, Vinnakota C, Waldvogel HJ, Faull RL, Kwakowsky A. Towards a Better Understanding of GABAergic Remodeling in Alzheimer\u2019s Disease. Int J Mol Sci. 2017;18:1813.","journal-title":"Int J Mol Sci"},{"key":"8520_CR62","doi-asserted-by":"crossref","unstructured":"Calma AD, van den Bos M, Pavey N, Santos Silva C, Menon P, Vucic S Physiological biomarkers of upper motor neuron dysfunction in ALS. Brain Sci. 2024;14:760.","DOI":"10.3390\/brainsci14080760"},{"key":"8520_CR63","doi-asserted-by":"crossref","unstructured":"Lee SE, Lee Y, Lee GH. The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain. Arch Pharm Res. 2019;42:1031\u20139.","DOI":"10.1007\/s12272-019-01196-z"},{"key":"8520_CR64","doi-asserted-by":"publisher","unstructured":"Venugopal S, Ghulam-jhelani Z, Simmons D, Chandler SH. Diminished GAD67 terminals and ambient GABA inhibition associated with reduced motor neuron recruitment threshold in the SOD1G93A ALS mouse. bioRxiv. 2021. https:\/\/doi.org\/10.1101\/2021.12.16.473041.","DOI":"10.1101\/2021.12.16.473041"},{"key":"8520_CR65","doi-asserted-by":"crossref","unstructured":"Fujihara K. Genetic deletion of the 67-kDa isoform of glutamate decarboxylase alters conditioned fear behavior in rats. FEBS Open Bio. 2021;11:340\u201353.","DOI":"10.1002\/2211-5463.13065"},{"key":"8520_CR66","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.cub.2014.01.022","volume":"24","author":"ES Peled","year":"2014","unstructured":"Peled ES, Newman ZL, Isacoff EY. Evoked and spontaneous transmission favored by distinct sets of synapses. Curr Biol. 2014;24:484\u201393.","journal-title":"Curr Biol"},{"key":"8520_CR67","doi-asserted-by":"publisher","first-page":"17253","DOI":"10.1523\/JNEUROSCI.3334-13.2013","volume":"33","author":"JE Melom","year":"2013","unstructured":"Melom JE, Akbergenova Y, Gavornik JP, Littleton JT. Spontaneous and evoked release are independently regulated at individual active zones. J Neurosci. 2013;33:17253\u201363.","journal-title":"J Neurosci"},{"key":"8520_CR68","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/nn.2317","volume":"12","author":"NB Fredj","year":"2009","unstructured":"Fredj NB, Burrone J. A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse. Nat Neurosci. 2009;12:751\u20138.","journal-title":"Nat Neurosci"},{"key":"8520_CR69","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1152\/jn.00325.2002","volume":"89","author":"HX Chen","year":"2003","unstructured":"Chen HX, Roper SN. Reduction of spontaneous inhibitory synaptic activity in experimental heterotopic gray matter. J Neurophysiol. 2003;89:150\u20138.","journal-title":"J Neurophysiol"},{"key":"8520_CR70","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2022.102553","volume":"75","author":"L Chen","year":"2022","unstructured":"Chen L, Li X, Tjia M, Thapliyal S. Homeostatic plasticity and excitation-inhibition balance: The good, the bad, and the ugly. Curr Opin Neurobiol. 2022;75:102553.","journal-title":"Curr Opin Neurobiol"},{"key":"8520_CR71","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1073\/pnas.1307784111","volume":"111","author":"MA Howard","year":"2014","unstructured":"Howard MA, Rubenstein JLR, Baraban SC. Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. Proc Natl Acad Sci USA. 2014;111:492\u20137.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8520_CR72","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.neuron.2015.07.033","volume":"87","author":"SB Nelson","year":"2015","unstructured":"Nelson SB, Valakh V. Excitatory\/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron. 2015;87:684\u201398.","journal-title":"Neuron"},{"key":"8520_CR73","doi-asserted-by":"crossref","unstructured":"Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, et al. The Vesicular GABA Transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic Neurons. J Neurosci. 1998;18:9733\u201350.","DOI":"10.1523\/JNEUROSCI.18-23-09733.1998"},{"key":"8520_CR74","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1111\/jnc.12393","volume":"127","author":"N Juge","year":"2013","unstructured":"Juge N, Omote H, Moriyama Y. Vesicular GABA transporter (VGAT) transports \u03b2-alanine. J Neurochem. 2013;127:482\u20136.","journal-title":"J Neurochem"},{"key":"8520_CR75","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1124\/mol.111.076083","volume":"81","author":"MH Yamada","year":"2012","unstructured":"Yamada MH, Nishikawa K, Kubo K, Yanagawa Y, Saito S. Impaired glycinergic synaptic transmission and enhanced inflammatory pain in mice with reduced expression of vesicular GABA transporter (VGAT). Mol Pharmacol. 2012;81:610\u20139.","journal-title":"Mol Pharmacol"},{"key":"8520_CR76","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1126\/science.1060342","volume":"293","author":"F Pouille","year":"2001","unstructured":"Pouille F, Scanziani M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science. 2001;293:1159\u201363.","journal-title":"Science"},{"key":"8520_CR77","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.neuron.2011.09.027","volume":"72","author":"JS Isaacson","year":"2011","unstructured":"Isaacson JS, Scanziani M. How inhibition shapes cortical activity. Neuron. 2011;72:231\u201343.","journal-title":"Neuron"},{"key":"8520_CR78","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1093\/brain\/awaa034","volume":"143","author":"CS Khademullah","year":"2020","unstructured":"Khademullah CS, Aqrabawi AJ, Place KM, Dargaei Z, Liang X, Pressey JC, et al. Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis. Brain. 2020;143:800\u201310.","journal-title":"Brain"},{"key":"8520_CR79","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.neuron.2019.10.008","volume":"105","author":"ZRS Duan","year":"2020","unstructured":"Duan ZRS, Che A, Chu P, Modol L, Bollmann Y, Babij R, et al. GABAergic restriction of network dynamics regulates interneuron survival in the developing cortex. Neuron. 2020;105:75\u201392.e5.","journal-title":"Neuron"},{"key":"8520_CR80","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/35097509","volume":"2","author":"O Mar\u00edn","year":"2001","unstructured":"Mar\u00edn O, Rubenstein JL. A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci. 2001;2:780\u201390.","journal-title":"Nat Rev Neurosci"},{"key":"8520_CR81","doi-asserted-by":"publisher","first-page":"5166","DOI":"10.1093\/cercor\/bhz055","volume":"29","author":"T Qureshi","year":"2019","unstructured":"Qureshi T, S\u00f8rensen C, Berghuis P, Jensen V, Dobszay MB, Farkas T, et al. The Glutamine Transporter Slc38a1 Regulates GABAergic neurotransmission and synaptic plasticity. Cereb Cortex. 2019;29:5166\u201379.","journal-title":"Cereb Cortex"},{"key":"8520_CR82","doi-asserted-by":"crossref","unstructured":"Romano G, Holodkov N, Klima R, Feiguin F. TDP-43 regulates GAD1 mRNA splicing and GABA signaling in Drosophila CNS. Sci Rep [Internet]. 2021;11:1\u20138","DOI":"10.1038\/s41598-021-98241-z"},{"key":"8520_CR83","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1002\/glia.20106","volume":"49","author":"B Cubelos","year":"2005","unstructured":"Cubelos B, Gonz\u00e1lez-Gonz\u00e1lez IM, Gim\u00e9nez C, Zafra F. Amino acid transporter SNAT5 localizes to glial cells in the rat brain. Glia. 2005;49:230\u201344.","journal-title":"Glia"},{"key":"8520_CR84","doi-asserted-by":"crossref","unstructured":"Kilb W, Kirischuk S. GABA Release from astrocytes in health and disease. Int J Mol Sci. 2022;23:15859.","DOI":"10.3390\/ijms232415859"},{"key":"8520_CR85","doi-asserted-by":"crossref","unstructured":"Sidoryk-W\u0119grzynowicz M, Adamiak K, Stru\u017cy\u0144ska L. Astrocyte-neuron interaction via the glutamate-glutamine cycle and its dysfunction in tau-dependent neurodegeneration. Int J Mol Sci. 2024;25:3050.","DOI":"10.3390\/ijms25053050"},{"key":"8520_CR86","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2025.106849","volume":"207","author":"A Hassan","year":"2025","unstructured":"Hassan A, di Vito R, Nuzzo T, Vidali M, Carlini MJ, Yadav S, et al. Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy. Neurobiol Dis. 2025;207:106849.","journal-title":"Neurobiol Dis"},{"key":"8520_CR87","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1038\/nm.3639","volume":"20","author":"S Jo","year":"2014","unstructured":"Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer\u2019s disease. Nat Med. 2014;20:886\u201396.","journal-title":"Nat Med"},{"key":"8520_CR88","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nmd.2024.03.002","volume":"37","author":"NC Cottam","year":"2024","unstructured":"Cottam NC, Harrington MA, Schork PM, Sun J. No significant sex differences in incidence or phenotype for the SMN\u03947 mouse model of spinal muscular atrophy. Neuromuscul Disord. 2024;37:13\u201322.","journal-title":"Neuromuscul Disord"},{"key":"8520_CR89","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.166063","volume":"1867","author":"NN Singh","year":"2021","unstructured":"Singh NN, Hoffman S, Reddi PP, Singh RN. Spinal muscular atrophy: Broad disease spectrum and sex-specific phenotypes. Biochim Biophys acta Mol basis Dis. 2021;1867:166063.","journal-title":"Biochim Biophys acta Mol basis Dis"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08520-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08520-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08520-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T08:03:45Z","timestamp":1774598625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08520-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":89,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8520"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08520-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]},"assertion":[{"value":"1 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"285"}}