FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4380853957> ?p ?o ?g. }

• W4380853957 abstract "•Increased molecular layer interneuron (MLIN) activity drives SCA1 pathophysiology•Inhibition of MLIN ameliorates network and behavioral SCA1 phenotypes•Mimicking MLIN hyperexcitability in healthy mice generates SCA1-like pathophysiology•MLIN hyperexcitability is conserved in human SCA1 patient-derived GABAergic neurons Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1. Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1. The mechanisms underlying the major neurodegenerative diseases (NDs) are still poorly understood. An enigmatic but uniform finding in patients and murine models of NDs is the early alteration in excitability of vulnerable neuronal populations and changes in the corresponding neuronal circuitry.1Leroy F. Zytnicki D. Is hyperexcitability really guilty in amyotrophic lateral sclerosis?.Neural Regen. Res. 2015; 10: 1413-1415https://doi.org/10.4103/1673-5374.165308Crossref Scopus (18) Google Scholar,2Roselli F. Caroni P. From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases.Neuron. 2015; 85: 901-910https://doi.org/10.1016/j.neuron.2014.12.063Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar For instance, in spinal muscular atrophy, motoneurons (MNs) become hyperexcitable,3Mentis G.Z. Blivis D. Liu W. Drobac E. Crowder M.E. Kong L. Alvarez F.J. Sumner C.J. O’Donovan M.J. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy.Neuron. 2011; 69: 453-467https://doi.org/10.1016/j.neuron.2010.12.032Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar whereas in amyotrophic lateral sclerosis, spinal MNs become hypoexcitable, losing their ability to fire repetitively.4Leroy F. Lamotte d’Incamps B. Imhoff-Manuel R.D. Zytnicki D. Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis.eLife. 2014; 3https://doi.org/10.7554/eLife.04046Crossref Scopus (103) Google Scholar,5Saxena S. Roselli F. Singh K. Leptien K. Julien J.P. Gros-Louis F. Caroni P. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.Neuron. 2013; 80: 80-96https://doi.org/10.1016/j.neuron.2013.07.027Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Similarly, in spinocerebellar ataxia type-1 (SCA1) and type-2 (SCA2), Purkinje neurons (PNs) show a reduction in the firing rate at presymptomatic stages.6Barnes J.A. Ebner B.A. Duvick L.A. Gao W. Chen G. Orr H.T. Ebner T.J. Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice.J. Neurosci. 2011; 31: 12778-12789https://doi.org/10.1523/JNEUROSCI.2579-11.2011Crossref PubMed Scopus (62) Google Scholar,7Hansen S.T. Meera P. Otis T.S. Pulst S.M. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.Hum. Mol. Genet. 2013; 22: 271-283https://doi.org/10.1093/hmg/dds427Crossref PubMed Scopus (118) Google Scholar The precise cause of these alterations and whether they are involved in the degenerative process remains unknown. SCA1 is a devastating, incurable ND due to the expansion of a polyglutamine (PolyQ) repeat within the ubiquitously expressed protein Ataxin-1, leading to the premature degeneration of cerebellar PNs.8Paulson H.L. Shakkottai V.G. Clark H.B. Orr H.T. Polyglutamine spinocerebellar ataxias — from genes to potential treatments.Nat. Rev. Neurosci. 2017; 18: 613-626https://doi.org/10.1038/nrn.2017.92Crossref PubMed Scopus (210) Google Scholar One critical open question is why cerebellar PNs selectively degenerate in SCA1. In most NDs, multiple cell types within neuronal circuits throughout the CNS are affected, and crucial synaptic and network dysfunction might occur before the appearance of overt pathology.9Braz B.Y. Wennagel D. Ratié L. de Souza D.A.R. Deloulme J.C. Barbier E.L. Buisson A. Lanté F. Humbert S. Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice.Science. 2022; 377: eabq5011https://doi.org/10.1126/science.abq5011Crossref PubMed Scopus (8) Google Scholar,10Pradhan J. Bellingham M.C. Neurophysiological mechanisms underlying cortical hyper-excitability in amyotrophic lateral sclerosis: a review.Brain Sci. 2021; 11: 549https://doi.org/10.3390/brainsci11050549Crossref Scopus (6) Google Scholar,11Ramírez-Jarquín U.N. Lazo-Gómez R. Tovar-y-Romo L.B. Tapia R. Spinal inhibitory circuits and their role in motor neuron degeneration.Neuropharmacology. 2014; 82: 101-107https://doi.org/10.1016/j.neuropharm.2013.10.003Crossref PubMed Scopus (27) Google Scholar Moreover, it has been increasingly acknowledged that non-cell autonomous impairments, such as early circuit-mediated alterations, might critically govern or even trigger the pathology in disease-vulnerable neurons.12Gunes Z.I. Kan V.W.Y. Ye X. Liebscher S. Exciting complexity: the role of motor circuit elements in ALS pathophysiology.Front. Neurosci. 2020; 14: 573https://doi.org/10.3389/fnins.2020.00573Crossref Scopus (23) Google Scholar Previous studies by us and others highlighted the importance of early circuit-related changes within the cerebellum that affect PN activity in SCA1.6Barnes J.A. Ebner B.A. Duvick L.A. Gao W. Chen G. Orr H.T. Ebner T.J. Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice.J. Neurosci. 2011; 31: 12778-12789https://doi.org/10.1523/JNEUROSCI.2579-11.2011Crossref PubMed Scopus (62) Google Scholar,13Edamakanti C.R. Do J. Didonna A. Martina M. Opal P. Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1.J. Clin. Invest. 2018; 128: 2252-2265https://doi.org/10.1172/JCI96765Crossref PubMed Scopus (34) Google Scholar,14Ruegsegger C. Stucki D.M. Steiner S. Angliker N. Radecke J. Keller E. Zuber B. Rüegg M.A. Saxena S. Impaired mTORC1-dependent expression of Homer-3 influences SCA1 pathophysiology.Neuron. 2016; 89: 129-146https://doi.org/10.1016/j.neuron.2015.11.033Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Mainly, excitatory synaptic inputs onto PNs from climbing fibers (CFs), but not from parallel fibers (PFs), are altered presymptomatically, leading to reduced CF-PN synaptic strength and subsequent alterations in PN excitability. This suggests the existence of early, selectively vulnerable circuit components, upstream of the affected PNs.6Barnes J.A. Ebner B.A. Duvick L.A. Gao W. Chen G. Orr H.T. Ebner T.J. Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice.J. Neurosci. 2011; 31: 12778-12789https://doi.org/10.1523/JNEUROSCI.2579-11.2011Crossref PubMed Scopus (62) Google Scholar,14Ruegsegger C. Stucki D.M. Steiner S. Angliker N. Radecke J. Keller E. Zuber B. Rüegg M.A. Saxena S. Impaired mTORC1-dependent expression of Homer-3 influences SCA1 pathophysiology.Neuron. 2016; 89: 129-146https://doi.org/10.1016/j.neuron.2015.11.033Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,15Duvick L. Barnes J. Ebner B. Agrawal S. Andresen M. Lim J. Giesler G.J. Zoghbi H.Y. Orr H.T. SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776.Neuron. 2010; 67: 929-935https://doi.org/10.1016/j.neuron.2010.08.022Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar,16Ebner B.A. Ingram M.A. Barnes J.A. Duvick L.A. Frisch J.L. Clark H.B. Zoghbi H.Y. Ebner T.J. Orr H.T. Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum.J. Neurosci. 2013; 33: 5806-5820https://doi.org/10.1523/JNEUROSCI.6311-11.2013Crossref PubMed Scopus (37) Google Scholar Most previous studies were, however, conducted in slice cultures, allowing only limited insight into how cerebellar circuit elements and entire networks are affected in a spatiotemporal manner in animals by these described molecular and synaptic alterations. We hypothesized that PolyQ-repeat expansions have a more widespread impact on cerebellar circuits, thereby altering excitatory/inhibitory (E/I) balance, compromising sensorimotor functions, and ultimately triggering PN degeneration. Notably, PN activity is tightly shaped by GABAergic inhibitory molecular layer interneurons (MLINs).17Kim J. Augustine G.J. Molecular layer interneurons: key elements of cerebellar network computation and behavior.Neuroscience. 2021; 462: 22-35https://doi.org/10.1016/j.neuroscience.2020.10.008Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Although MLINs do not degenerate in SCA1,18Vig P.J. Fratkin J.D. Desaiah D. Currier R.D. Subramony S.H.. Decreased parvalbumin immunoreactivity in surviving Purkinje cells of patients with spinocerebellar ataxia-1.Neurology. 1996; 47: 249-253https://doi.org/10.1212/wnl.47.1.249Crossref PubMed Google Scholar they might still contribute to PN degeneration. First in vitro evidence for an involvement of MLINs in SCA1 pathology was provided by Edamakanti and colleagues, who identified the hyperproliferation of mutant cerebellar stem cells, preferentially differentiating into GABAergic interneurons, thus enhancing GABAergic synaptic inputs onto PNs.13Edamakanti C.R. Do J. Didonna A. Martina M. Opal P. Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1.J. Clin. Invest. 2018; 128: 2252-2265https://doi.org/10.1172/JCI96765Crossref PubMed Scopus (34) Google Scholar However, the longitudinal molecular, cellular, and circuit-level consequences of such synaptic alterations remain unclear. Here, combining in vivo two-photon calcium imaging in behaving knockin mice, harboring an expansion of 154 CAG repeats in the endogenous Ataxin-1 mouse locus (termed Sca1 throughout) together with chemogenetics, histological, ultrastructural, and MLIN-specific proteomic analyses, we demonstrate that neurons within the cerebellar network are differentially affected by the PolyQ expansion. Early impairments mainly involve alterations in the MLIN population, rendering them hyperexcitable, thereby affecting their response properties and compromising coding space in mice. Additionally, MLIN-selective proteomics from Sca1 mice revealed a disease-linked molecular signature, accounting for the observed changes in mutant MLIN functionality. Notably, this signature was conserved within human SCA1 patient-derived GABAergic neurons. Our results thus indicate that at the circuit level, molecular changes within mutant MLINs govern early cerebellar network dysfunction, promoting PNs degeneration in SCA1. To assess circuit-level deficits during the early symptomatic phase in postnatal (P) day 60 Sca1 mice, we performed two-photon calcium imaging in behaving mice, running on a spherical treadmill (Figures 1A and S1). By expressing the genetically encoded calcium indicator GCaMP7s, we simultaneously monitored activity of the three main inhibitory neuronal subtypes in the cerebellar cortex, namely, MLINs, PNs, and morphologically putative Golgi cells (Gol), while mice were maneuvering in a virtual environment (VR), with the locomotion speed being represented by the visual flow of the VR (feedback [fb]) or running in darkness (Figures 1A and 1B). These recordings revealed differential impairments of baseline fluorescence (indicative of alterations in resting cytoplasmic calcium concentrations), neuronal activity levels, and response properties of the different neuronal types (Figures 1C and 1D). As the typical instantaneous firing rate of these cell types exceeds the temporal resolution of the calcium indicator, but the fluorescence signal still scales with overall neuronal firing,19Chen T.W. Wardill T.J. Sun Y. Pulver S.R. Renninger S.L. Baohan A. Schreiter E.R. Kerr R.A. Orger M.B. Jayaraman V. et al.Ultrasensitive fluorescent proteins for imaging neuronal activity.Nature. 2013; 499: 295-300https://doi.org/10.1038/nature12354Crossref PubMed Scopus (3773) Google Scholar,20Dana H. Sun Y. Mohar B. Hulse B.K. Kerlin A.M. Hasseman J.P. Tsegaye G. Tsang A. Wong A. Patel R. et al.High-performance calcium sensors for imaging activity in neuronal populations and microcompartments.Nat. Methods. 2019; 16: 649-657https://doi.org/10.1038/s41592-019-0435-6Crossref PubMed Scopus (448) Google Scholar we assessed neuronal activity by computing the area under curve of the ΔF/F trace. We found that MLINs in Sca1 mice had not only a significantly lower baseline fluorescence (Figure 1E) but were also more active during quiet wakefulness (QW) during fb and darkness (Figure 1F). Conversely, we did not observe any changes in baseline fluorescence and a decrease in spontaneous neuronal activity levels (i.e., neuronal activity occurring during stationary epochs, measured as area under the curve [AUC]/min) during QW in Gol (Figures 1G and 1H) or PNs (Figures 1I and 1J). Moreover, we found a strong increase in the response to locomotion (Figures 1K–1M) selectively in MLINs in Sca1 (Figure 1N) and more MLINs being running responsive (Figure 1O). In contrast to MLIN hyperresponsiveness, Gol in Sca1 were driven less by locomotion (Figure 1P) and displayed no change in the fraction of running responsive neurons (Figure 1Q). At this early disease stage, no alterations in the response to locomotion in PNs was detected (Figures 1R and 1S). However, the number of Gol and PNs captured in this study are considerably lower than those of MLINs; thus, we may potentially underestimate alterations of these neuronal populations. Recording the same neurons under anesthesia further corroborated these findings (Figures S2A–S2D). We found a strong reduction in the baseline fluorescence of MLINs in Sca1 mice (Figure S2E), whereas baseline fluorescence was neither altered in Gol (Figure S2F) nor PNs (Figure S2G). We again observed an increase in spontaneous neuronal activity of MLINs (Figure S2H) but a decrease in Gol activity (Figure S2I) and no change in spontaneous PN activity in P60 Sca1 mice (Figure S2J). Despite lacking the temporal resolution to resolve the high instantaneous pacemaker firing activities of 40–60 Hz,21Raman I.M. Bean B.P. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons.J. Neurosci. 1999; 19: 1663-1674https://doi.org/10.1523/JNEUROSCI.19-05-01663.1999Crossref PubMed Google Scholar larger fluctuations in the PN fluorescence traces occur, likely caused by pauses in simple spike firing.22Ramirez J.E. Stell B.M. Calcium imaging reveals coordinated simple spike pauses in populations of cerebellar Purkinje cells.Cell Rep. 2016; 17: 3125-3132https://doi.org/10.1016/j.celrep.2016.11.075Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Those fluctuations, however, did not differ between wild-type (WT) and Sca1 mice. Because GCaMP only allows for an approximation of calcium levels, we performed experiments using the ratiometric calcium indicator Twitch2B,23Thestrup T. Litzlbauer J. Bartholomäus I. Mues M. Russo L. Dana H. Kovalchuk Y. Liang Y. Kalamakis G. Laukat Y. et al.Optimized ratiometric calcium sensors for functional in vivo imaging of neurons and T lymphocytes.Nat. Methods. 2014; 11: 175-182https://doi.org/10.1038/nmeth.2773Crossref PubMed Scopus (245) Google Scholar (Figures S3A–S3C), enabling more accurate measurements of actual calcium concentrations independent of expression levels. This analysis confirmed the reduced resting calcium concentration of MLINs in anesthetized SCA1 mice (Figure S3D), and also unraveled reduced levels in Gol, but not in PNs at this early symptomatic stage (Figures S3E and S3F). We assessed neuronal activity levels and again found increased activity in MLINs in Sca1 (Figure S3G); however, we found unchanged Gol activity (Figure S3H) and a slight, yet significant, increase in PNs (Figure S3I). As in PNs, we may mainly detect fluctuations in the calcium signal due to pauses in firing and complex spikes. Consequently, reduced pacemaker activity (as described for PNs in Sca124Dell’Orco J.M. Wasserman A.H. Chopra R. Ingram M.A.C. Hu Y.S. Singh V. Wulff H. Opal P. Orr H.T. Shakkottai V.G. Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability.J. Neurosci. 2015; 35: 11292-11307https://doi.org/10.1523/JNEUROSCI.1357-15.2015Crossref PubMed Scopus (72) Google Scholar), potentially even appears as greater fluctuations in the fluorescent signal. To probe for probable impairments of sensorimotor integration, we compared neuronal activity levels during fb with those in darkness, (Figure S4A) and observed a strong linear correlation. However, we found Sca1 MLINs displayed a leftward shift in the ratio of fb/dark activity, indicating alterations in sensorimotor integration (Figure S4A). Conversely, we found Gol to be less active in Sca1 mice during fb and darkness (Figure S4B), whereas Sca1 PNs were slightly more active during fb (Figure S4C). We also probed sensorimotor integration by assessing neuronal responses to an air puff, driving sensory, arousal, and startle-response signals25Gurnani H. Silver R.A. Multidimensional population activity in an electrically coupled inhibitory circuit in the cerebellar cortex.Neuron. 2021; 109 (1739.e8–1753.e8)https://doi.org/10.1016/j.neuron.2021.03.027Abstract Full Text Full Text PDF Scopus (7) Google Scholar (Figures S4D–S4F). We observed a significant increase in neuronal activity in mutant MLINs (Figure S4G), a decreased response in Gol (Figure S4H), and an increase in PNs (Figure S4I). Together, these data show that neuronal dysfunction in Sca1 mice is based on a combination of altered spontaneous activity and differentially impaired responsiveness to sensorimotor signals. Importantly, the cell type showing the strongest change in Sca1 mice are MLINs, displaying increased activity levels, arguing for MLINs being hyperexcitable already in early symptomatic Sca1 mice. To gain insight into cerebellar network dysfunction in early symptomatic Sca1 mice, we investigated neural network representations of behavioral states and their distinctiveness. Several neuronal populations in the cerebellar cortex encode various sensorimotor signals in a multidimensional manner.25Gurnani H. Silver R.A. Multidimensional population activity in an electrically coupled inhibitory circuit in the cerebellar cortex.Neuron. 2021; 109 (1739.e8–1753.e8)https://doi.org/10.1016/j.neuron.2021.03.027Abstract Full Text Full Text PDF Scopus (7) Google Scholar,26Cayco-Gajic N.A. Silver R.A. Re-evaluating circuit mechanisms underlying pattern separation.Neuron. 2019; 101: 584-602https://doi.org/10.1016/j.neuron.2019.01.044Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar,27Lanore F. Cayco-Gajic N.A. Gurnani H. Coyle D. Silver R.A. Cerebellar granule cell axons support high-dimensional representations.Nat. Neurosci. 2021; 24: 1142-1150https://doi.org/10.1038/s41593-021-00873-xCrossref PubMed Scopus (14) Google Scholar We chose a principal-component analysis (PCA)-based approach to investigate the dimensionality of the population dynamics in behaving mice. We assembled an input matrix, consisting of 0-centered, Z scored ΔF/F traces of all cells identified in a given field of view (FOV) and aligned it with the recordings of running speed, whisking, pupil width, and applied air puffs (Figure 2A). Analyses of the variance explained of the population activity revealed a multidimensional nature (Figure 2B). The first component (PC1) alone explained ∼50% of the variance of the population activity in WT and Sca1 (Figure 2C), dominated by locomotion and whisking. However, in Sca1 mice, the variance of PC1 explained by locomotion, air puff, and whisking was reduced compared with WT (Figure 2D). Cell-type-specific regression analyses of PC1 revealed a significant reduction of the behavioral parameters for MLINs only, whereas for Gol it was mainly the contribution of the air-puff-representation that was affected (Figure 2D). In PNs, no significant difference in the encoding of behavioral parameters was found (Figure 2D). We also assessed the information content captured in PC2, which still contributed ∼16% to the overall variance of the population activity (WT: 15.95% ± 4%, Sca1: 8.44% ± 2.6% of the variance). PC2 was also driven by locomotion as a single parameter but mainly captured all parameters combined, thus, the difference between active and quiescent phases (Figure S5). In contrast to PC1, we could not detect any differences in the variance explained by the individual behavioral parameters between WT and Sca1 mice (Figure S5). Neuronal activity patterns were multi-dimensional, consisting of at least 10 components. We thus asked how the geometry of these neuronal representations might be affected in Sca1 mice. We computed the manifolds by projecting the multi-dimensional neuronal population activity to low-dimensional space, consisting of the first three components.27Lanore F. Cayco-Gajic N.A. Gurnani H. Coyle D. Silver R.A. Cerebellar granule cell axons support high-dimensional representations.Nat. Neurosci. 2021; 24: 1142-1150https://doi.org/10.1038/s41593-021-00873-xCrossref PubMed Scopus (14) Google Scholar,28Gobbo F. Mitchell-Heggs R. Tse D. Changes in brain activity and connectivity as memories age.Cogn. Neurosci. 2022; 13: 141-143https://doi.org/10.1080/17588928.2022.2076076Crossref Scopus (0) Google Scholar,29Vyas S. Golub M.D. Sussillo D. Shenoy K.V. Computation through neural population dynamics.Annu. Rev. Neurosci. 2020; 43: 249-275https://doi.org/10.1146/annurev-neuro-092619-094115Crossref PubMed Scopus (117) Google Scholar In WT mice, two distinct structures emerged, separating QW from locomotion (Figure 2E), corroborating previous reports.27Lanore F. Cayco-Gajic N.A. Gurnani H. Coyle D. Silver R.A. Cerebellar granule cell axons support high-dimensional representations.Nat. Neurosci. 2021; 24: 1142-1150https://doi.org/10.1038/s41593-021-00873-xCrossref PubMed Scopus (14) Google Scholar Notably, the PC space representing QW was reduced in Sca1 mice (Figure 2F), and the two subspaces were less segregated, as illustrated by the decreased Euclidean distance (Figure 2F). Together these data highlight a compromised encoding capacity of the cerebellar circuit in early symptomatic Sca1 mice, an effect primarily driven by MLIN dysfunction. To assess whether these deviations in neuronal function persist throughout the disease course, we performed similar experiments in P200 Sca1 mice (Figures S6A and S6B). Under anesthesia, we observed a small but significant decrease in baseline fluorescence in MLINs (Figure S6C), no change in Gol (Figure S6D), and a pronounced increase in baseline fluorescence in PNs (Figure S6E), indicating a severe increase in cytoplasmic calcium levels in PNs at late disease stages. Neuronal activity of MLINs under anesthesia was still significantly increased (Figure S6F), which was also true for Gol (Figure S6G), whereas in PNs, we found reduced calcium fluctuations (Figure S6H). These findings were in line with the increased MLIN activity seen in awake mice during QW (Figure S6I). However, in awake mice, we still observed a decrease in Gol activity (Figure S6J), which could reflect the higher inhibitory tone during wakefulness, i.e., abolished under anesthesia, thereby potentially unmasking changes in intrinsic excitability. In PNs, we again observed decreased calcium fluctuations (Figure S6K). We quantified the response to locomotion and found a strong hyperresponsiveness of MLINs to running (Figure S6L), a hyporesponsiveness in Gol (Figure S6M), and a non-significant trend toward compromised locomotion responses in PNs (Figure S6N). Altogether, these data reveal that the observed hyperexcitability of MLINs remains conserved throughout the disease course in Sca1 mice. Given previous reports indicating hyperexcitability in PN dendrites as a critical contributor to PN degeneration,30Chopra R. Bushart D.D. Cooper J.P. Yellajoshyula D. Morrison L.M. Huang H. Handler H.P. Man L.J. Dansithong W. Scoles D.R. et al.Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.Hum. Mol. Genet. 2020; 29: 3249-3265https://doi.org/10.1093/hmg/ddaa212Crossref Scopus (12) Google Scholar we assessed PN dendritic calcium signals, likely reflecting complex spiking31Wagner M.J. Savall J. Hernandez O. Mel G. Inan H. Rumyantsev O. Lecoq J. Kim T.H. Li J.Z. Ramakrishnan C. et al.A neural circuit state change underlying skilled movements.Cell. 2021; 184 (3731.e21–3747.e21)https://doi.org/10.1016/j.cell.2021.06.001Abstract Full Text Full Text PDF Scopus (13) Google Scholar (Figures S7A and S7B). At P60, when no change in PN somata was observed yet, we already found evidence for increased dendritic excitability, seen in a higher fraction of active dendrites (i.e., dendrites displaying at least one clear calcium transient, Figure S7C), and an increase in dendritic calcium signals in Sca1 mice (Figures S7D and S7E). These changes persisted until late disease stages (P200), with more active dendrites (Figure S7F) and higher activity levels (Figures S7G and S7H). We sought to gain insight into the mechanisms governing early MLIN hyperexcitability in SCA1. By P30 cerebellar cortex is matured; therefore, we evaluated the expression of the calcium-binding protein parvalbumin (PV), a well-established MLIN marker, at P30, when Sca1 mice lack motor incoordination (Figure S8A). Additionally, PV-expression levels are an indicator of neuronal activity, coinciding with plasticity-related learning processes.32Donato F. Rompani S.B. Caroni P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning.Nature. 2013; 504: 272-276https://doi.org/10.1038/nature12866Crossref PubMed Scopus (449) Google Scholar,33Donato F. Chowdhury A. Lahr M. Caroni P. Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning.Neuron. 2015; 85: 770-786https://doi.org/10.1016/j.neuron.2015.01.011Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Although the majority of P30, WT MLINs expressed medium levels of PV, 32% of MLINs presented high levels of PV in Sca1. The fraction of mutant MLINs expressing high levels of PV increased as a function of disease progression with 49% at P90 and 60% at P200 (Figure 3A). To exclude that the observed increase in mutant MLIN numbers, displaying high levels of PV was due to MLIN degeneration, we quantified the number of MLINs. Notably, until the end-stage, mutant MLIN numbers remained unchanged, suggesting that the early, yet gradual, increase in PV levels, reflect changes in MLIN activity (Figure 3B). Furthermore, we examined PV levels in interneurons located in the primary motor cortex, a region involved in movement execution. No change in PV-expression levels or numbers was observed in Sca1 (Figures S8B and S8C), suggesting that alterations in PV-expression levels were restricted to the cerebellum. Next, we assessed the distribution of synaptic inputs onto MLINs and found that Sca1 MLINs displayed increased numbers of excitatory synapses, marked by the vesicular glutamate transporter 1 (VGluT1) (Figure 3C). Concomitantly, mutant MLINs received fewer vesicular GABA transporter (VGAT)-positive homotypic inhibitory inputs from adjacent interneurons (Figure 3C). Both alterations in E/I inputs onto MLINs persisted until late disease stage. Because altered E/I connectivity on MLINs" @default.
• W4380853957 created "2023-06-16" @default.
• W4380853957 creator A5005942989 @default.
• W4380853957 creator A5008502210 @default.
• W4380853957 creator A5016021743 @default.
• W4380853957 creator A5034143227 @default.
• W4380853957 creator A5040962580 @default.
• W4380853957 creator A5041522685 @default.
• W4380853957 creator A5049638970 @default.
• W4380853957 creator A5052441794 @default.
• W4380853957 creator A5053516116 @default.
• W4380853957 creator A5063666811 @default.
• W4380853957 creator A5065549960 @default.
• W4380853957 creator A5066123271 @default.
• W4380853957 creator A5076990798 @default.
• W4380853957 creator A5082772840 @default.
• W4380853957 creator A5092179657 @default.
• W4380853957 creator A5092179658 @default.
• W4380853957 creator A5092179659 @default.
• W4380853957 creator A5092179660 @default.
• W4380853957 date "2023-06-01" @default.
• W4380853957 modified "2023-09-25" @default.
• W4380853957 title "Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1" @default.
• W4380853957 cites W1531491702 @default.
• W4380853957 cites W1868105705 @default.
• W4380853957 cites W1969416829 @default.
• W4380853957 cites W1971793795 @default.
• W4380853957 cites W1979612107 @default.
• W4380853957 cites W1985248414 @default.
• W4380853957 cites W1986887325 @default.
• W4380853957 cites W1987278178 @default.
• W4380853957 cites W1990288633 @default.
• W4380853957 cites W1991280665 @default.
• W4380853957 cites W1999251867 @default.
• W4380853957 cites W2003320905 @default.
• W4380853957 cites W2006656241 @default.
• W4380853957 cites W2006900120 @default.
• W4380853957 cites W2017555154 @default.
• W4380853957 cites W2025806474 @default.
• W4380853957 cites W2026193431 @default.
• W4380853957 cites W2029101220 @default.
• W4380853957 cites W2031133527 @default.
• W4380853957 cites W2035357631 @default.
• W4380853957 cites W2038566549 @default.
• W4380853957 cites W2046213059 @default.
• W4380853957 cites W2056300681 @default.
• W4380853957 cites W2056540723 @default.
• W4380853957 cites W2058183189 @default.
• W4380853957 cites W2064025488 @default.
• W4380853957 cites W2069072617 @default.
• W4380853957 cites W2075312701 @default.
• W4380853957 cites W2080752012 @default.
• W4380853957 cites W2090875072 @default.
• W4380853957 cites W2100065191 @default.
• W4380853957 cites W2101970831 @default.
• W4380853957 cites W2104431345 @default.
• W4380853957 cites W2105584468 @default.
• W4380853957 cites W2109164945 @default.
• W4380853957 cites W2109902738 @default.
• W4380853957 cites W2110332747 @default.
• W4380853957 cites W2122598723 @default.
• W4380853957 cites W2125541859 @default.
• W4380853957 cites W2131045025 @default.
• W4380853957 cites W2133232170 @default.
• W4380853957 cites W2158305904 @default.
• W4380853957 cites W2161902422 @default.
• W4380853957 cites W2171332611 @default.
• W4380853957 cites W2203568037 @default.
• W4380853957 cites W2211432006 @default.
• W4380853957 cites W2228127492 @default.
• W4380853957 cites W2258965264 @default.
• W4380853957 cites W2291957660 @default.
• W4380853957 cites W2305929847 @default.
• W4380853957 cites W2332285039 @default.
• W4380853957 cites W2398841788 @default.
• W4380853957 cites W2414157977 @default.
• W4380853957 cites W2512791742 @default.
• W4380853957 cites W2527924176 @default.
• W4380853957 cites W2531764546 @default.
• W4380853957 cites W2562018078 @default.
• W4380853957 cites W2604185077 @default.
• W4380853957 cites W2724721383 @default.
• W4380853957 cites W2741612932 @default.
• W4380853957 cites W2747198643 @default.
• W4380853957 cites W2766211776 @default.
• W4380853957 cites W2789304331 @default.
• W4380853957 cites W2789586042 @default.
• W4380853957 cites W2796041814 @default.
• W4380853957 cites W2801290777 @default.
• W4380853957 cites W2802131146 @default.
• W4380853957 cites W2890496670 @default.
• W4380853957 cites W2918076437 @default.
• W4380853957 cites W2950849463 @default.
• W4380853957 cites W2969899571 @default.
• W4380853957 cites W2979485701 @default.
• W4380853957 cites W2995248183 @default.
• W4380853957 cites W3012706082 @default.
• W4380853957 cites W3033486727 @default.
• W4380853957 cites W3041725488 @default.
• W4380853957 cites W3081944676 @default.

• next