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Astrocytes Restore Connectivity and Synchronization in Dysfunctional Cerebellar Networks

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Astrocytes Restore Connectivity and Synchronization in Dysfunctional Cerebellar Networks Astrocytes restore connectivity and synchronization in dysfunctional cerebellar networks Sivan Kannera, Miri Goldinb,c, Ronit Galrona, Eshel Ben Jacobb,d,1, Paolo Bonifazib,c,e,2,3, and Ari Barzilaia,d,2,3 aDepartment of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel; bSchool of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel; cComputational Neuroimaging Laboratory, Biocruces Health Research Institute, Hospital Universitario Cruces, 48903 Baracaldo, Vizcaya, Spain; dSagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel; and eIkerbasque: The Basque Foundation for Science, 48013 Bilbao, Bizkaia, Spain Edited by Tullio Pozzan, University of Padova, Padova, Italy, and approved June 26, 2018 (received for review October 24, 2017) Evidence suggests that astrocytes play key roles in structural and neuronal synchronizations (NSs), a hallmark activity pattern of functional organization of neuronal circuits. To understand how the developing nervous system that could be observed in many astrocytes influence the physiopathology of cerebellar circuits, we different circuits in various species and in in vitro preparations cultured cells from cerebella of mice that lack the ATM gene. Mu- including primary neuronal cultures (11–13). tations in ATM are causative of the human cerebellar degenerative We report that the absence of Atm in neurons and astrocytes disease ataxia-telangiectasia. Cerebellar cultures grown from severely alters astrocyte morphology and the number of pre- −/− Atm mice had disrupted network synchronization, atrophied synaptic and postsynaptic puncta, disrupting NSs within cere- − − astrocytic arborizations, reduced autophagy levels, and higher bellar networks. Higher numbers of synaptic puncta in Atm / numbers of synapses per neuron than wild-type cultures. Chimeric networks relative to numbers in WT cultures were associated −/− circuitries composed of wild-type astrocytes and Atm neurons with lower levels of autophagy. These reported structural and were indistinguishable from wild-type cultures. Adult cerebellar functional anomalies were all rescued in chimeric neuronal − − characterizations confirmed disrupted astrocyte morphology, in- networks composed of Atm / neurons and WT astrocytes. In − − creased GABAergic synaptic markers, and reduced autophagy in contrast, cultures of WT neurons with Atm / astrocytes led to −/− − − Atm compared with wild-type mice. These results indicate that significant neuronal cell death. Characterizations of adult Atm / astrocytes can impact neuronal circuits at levels ranging from syn- cerebella similarly showed disrupted astrocyte morphology, up- aptic expression to global dynamics. regulated GABAergic markers, and dysregulated mTOR- mediated signaling and autophagy. These results, obtained in an astrocyte | neural circuit | synchronization | disease | ATM in vitro model system and confirmed in adult mice, demonstrate a possible role played by astrocytes in the physiopathological, rain degenerative diseases (BDDs) disrupt brain function by structural, and functional organization of the cerebellar circuits. Bimpairing the ability of specific neuronal circuitries to locally process (segregate) and distantly communicate (integrate) in- Results formation across brain-spanning networks (1, 2). At the neuronal Absence of Atm Impairs in Vitro Cerebellar Neuronal Network −/− circuit level, BDDs induce the loss of different cell types and Synchronizations. All Atm or WT astrocyte and neuronal cul- cellular functionality (2, 3) and alter circuit topology and dy- tures/networks referred to in the text were derived from single namics. Currently, it is unclear how particular diseases explicitly animals. A total of 80% of the cells in the primary cerebellar alter specific brain circuits and neuro-glial populations. In the last two decades, it has become appreciated that glial Significance cells play a critical role in BDDs (4). The symptoms of BDDs arise from pathological changes to neuro-glia interactions (5), Within the long-standing debate of whether glial cells con- NEUROSCIENCE leading to neuronal cell death, disrupted neuro-glia communi- tribute to neuronal circuits, we provide evidence of the impact cation, and impaired cell function (3), all of which affect global of astrocytes on the physiopathology and the structural–func- dynamics of brain circuitry. Astrocytes, a particular glial cell tional organization of cerebellar neuronal circuits derived from type, play key roles in regulating the pathophysiology of neuronal Atm-deficient mice. In vitro and adult mouse characterizations functions (6). Specifically, perisynaptic sheaths of astrocytes show how disrupted astrocyte morphology is associated with −/− cover the majority of synapses in the central nervous system and an increased presence of synaptic markers in Atm compared are essential for synaptogenesis, maturation, and maintenance with wild-type circuits, also related to reduce autophagy. Our of synapses (7). This structural–functional unit, also called the study is corroborated by an in vitro demonstration of how “tripartite synapse,” enables astrocytes to influence synaptic replenishment of neuronal circuits with healthy astrocytes can Atm−/− ’ communication via gliotransmission (5). restore neuronal circuits dynamics. In this work, we tested the hypothesis that neuronal circuit – Author contributions: S.K., P.B., and A.B. designed research; S.K., M.G., and R.G. per- dynamics were impacted as a consequence of disrupted neuron formed research; E.B.J. contributed new reagents/analytic tools; P.B. designed the soft- astrocyte physiology in a mouse model of the BDD that results ware and validated imaging data; S.K. and P.B. analyzed data; E.B.J., P.B. , and A.B. from a deficiency in Ataxia Telangiectasia Mutated (ATM) provided supervision; and S.K., P.B., and A.B. wrote the paper. protein. The gene encoding ATM is mutated in the human ge- The authors declare no conflict of interest. netic disease ataxia-telangiectasia (A-T) (8, 9). One of the most This article is a PNAS Direct Submission. devastating symptoms of A-T is the cerebellar ataxia, with sig- Published under the PNAS license. nificant loss of Purkinje and granule neurons in the cerebellum, 1Deceased June 5, 2015. that leads progressively to general motor dysfunction (10). 2P.B. and A.B. contributed equally to this work. We used primary cerebellar cultures grown from postnatal 3To whom correspondence may be addressed. Email: [email protected] or AriB@ −/− wild-type (WT) and Atm mice to study how Atm deficiency tauex.tau.ac.il. influences the structure and dynamics of cerebellar neuronal– This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. astrocyte circuits. We hypothesized that Atm deficiency impairs 1073/pnas.1718582115/-/DCSupplemental. the neuronal–astrocytic interactions underlying spontaneous Published online July 16, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1718582115 PNAS | July 31, 2018 | vol. 115 | no. 31 | 8025–8030 Downloaded by guest on September 23, 2021 cultures were granule neurons (NeuN-positive; n = 19) (14, 15). compared with WT cultures; in WT cultures, SSs were very The majority of the remaining cells were astrocytes (GFAP- and infrequent (Fig. 1E; P < 0.0001, MWU test). Vimentin-positive), with a small portion of only Vimentin- When analyzing the GS build-up, we observed that early acti- − − positive cells (oligodendrocytes and glia precursors) (refs. 16– vated cells repeatedly preceding the GS in WT and Atm / net- 18 and SI Appendix, Fig. S1 A and B). works represented 9 ± 1% (n = 28) and 13 ± 3% (n = 22) of the The spontaneous activities of cultured cerebellar networks active neuronal population, respectively, with no significant dif- − − derived from Atm / and WT mice were monitored by using ference between the two groups (SI Appendix, Fig. S3; P > 0.05, calcium-based imaging (Fig. 1). The calcium signals that origi- two-sample Kolmogorov–Smirnov test). Cells recruited in the SS − − nated from the neuronal activity were characterized by stereo- (n = 2,615 from 22 Atm / networks) were spatially closely lo- typical sharp calcium transients (on the order of a few dozens of cated, and this localization was significant compared with ran- milliseconds, abolished by tetrodotoxin; n = 3) and were gener- domly computationally generated SSs (SI Appendix,Fig.S4). ated and recorded from granule cell bodies (isolated or orga- No cell showed higher significant participation in SS since − − nized in multicellular clusters, as shown in SI Appendix, Fig. S1 recruitment frequencies were similar in the Atm / networks and C–H). Extended wider segmentation of calcium images includ- in randomly computationally generated sequences of SSs that ing astrocytic processes (SI Appendix, Figs. S1H and S2) con- preserved the recruited cellular populations (Kolmogorov– firmed the presence of fast calcium signals only in neuronal cells. Smirnov test, P > 0.05; Methods). Stereotypical slow calcium signals of astrocytes were rarely ob- served (and not included in the network analysis; Methods). The Absence of Atm Reduces Morphological Complexity of Astrocytes. neuronal calcium signals were mediated by glutamatergic synaptic Previous studies showed that astrocyte coverage of blood vessels − − connectivity, since they were blocked by an AMPA receptor is dramatically reduced in the retinas of Atm / mice (10). We antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxa-
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