Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in an autism mouse model

Abstract

The cerebellum is heavily connected with other brain regions, sub-serving not only motor but also nonmotor functions. Genetic mutations leading to cerebellar dysfunction are associated with mental diseases, but cerebellar outputs have not been systematically studied in this context. Here, we present three dimensional distributions of 50,168 target neurons of cerebellar nuclei (CN) from wild-type mice and Nlgn3^R451C mutant mice, a mouse model for autism. Our results derived from 36 target nuclei show that the projections from CN to thalamus, midbrain and brainstem are differentially affected by Nlgn3^R451C mutation. Importantly, Nlgn3^R451C mutation altered the innervation power of CN→zona incerta (ZI) pathway, and chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social defects in Nlgn3^R451C mice. Our study highlights potential role of cerebellar outputs in the pathogenesis of autism and provides potential new therapeutic strategy for this disease.

Keywords

cerebellum / thalamus / midbrain / large-scale tracing / autism

References

[1] Abdelgabar AR, Suttrup J, Broersen R et al. Action perception recruits the cerebellum and is impaired in patients with spinocerebellar ataxia. Brain 2019;142:3791–3805.

[2] Adorjan I, Ahmed B, Feher V et al. Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder. Brain 2017;140:2028–2040.

[3] Ahmadlou M, Houba JHW, van Vierbergen JFM et al. A cell type-specific cortico-subcortical brain circuit for investigatory and novelty-seeking behavior. Science 2021;372:eabe9681.

[4] Al Sagheer T, Haida O, Balbous A et al. Motor impairments correlate with social deficits and restricted neuronal loss in an environmental model of autism. Int J Neuropsychopharmacol 2018;21:871–882.

[5] Baudouin SJ, Gaudias J, Gerharz S et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 2012;338:128–132.

[6] Buckner RL. The cerebellum and cognitive function:25 years of insight from anatomy and neuroimaging. Neuron 2013;80:807–815.

[7] Carta I, Chen CH, Schott AL et al. Cerebellar modulation of the reward circuitry and social behavior. Science 2019;363:eaav0581.

[8] Chabrol FP, Blot A, Mrsic-Flogel TD. Cerebellar contribution to preparatory activity in motor neocortex. Neuron 2019;103:506–519.e4.

[9] Chen JY, Markowitz JE, Lilascharoen V et al. Flexible scaling and persistence of social vocal communication. Nature 2021;593:108–113.

[10] Chou XL, Wang X, Zhang ZG et al. Inhibitory gain modulation of defense behaviors by zona incerta. Nat Commun 2018;9:1151.

[11] Cupolillo D, Hoxha E, Faralli A et al. Autistic-like traits and cerebellar dysfunction in Purkinje cell PTEN knock-out mice. Neuropsychopharmacology 2016;41:1457–1466.

[12] Deverett B, Kislin M, Tank DW et al. Cerebellar disruption impairs working memory during evidence accumulation. Nat Commun 2019;10:3128.

[13] Fujita J, Kodama T, du Lac S. Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis. Elife 2020;9:e58613.

[14] Futai K, Doty CD, Baek B et al. Specific trans-synaptic interaction with inhibitory interneuronal neurexin underlies differential ability of neuroligins to induce functional inhibitory synapses. J Neurosci 2013;33:3612–3623.

[15] Gao Z, Davis C, Thomas AM et al. A cortico-cerebellar loop for motor planning. Nature 2018;563:113–116.

[16] Gibson JM, Vazquez AH, Yamashiro K et al. Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models. Cell Rep 2023;42:113533.

[17] Hoche F, Guell X, Vangel MG et al. The cerebellar cognitive affective/Schmahmann syndrome scale. Brain 2018;141:248–270.

[18] Hornberg H, Pérez-Garci E, Schreiner D et al. Rescue of oxytocin response and social behaviour in a mouse model of autism. Nature 2020;584:252–256.

[19] Inouye M, Murakami U. Temporal and spatial patterns of Purkinje cell formation in the mouse cerebellum. J Comp Neurol 1980;194:499–503.

[20] Isshiki M, Tanaka S, Kuriu T et al. Enhanced synapse remodelling as a common phenotype in mouse models of autism. Nat Commun 2014;5:4742.

[21] Jack A, Morris JP. Neocerebellar contributions to social perception in adolescents with autism spectrum disorder. Dev Cogn Neurosci 2014;10:77–92.

[22] Kebschull JM, Richman EB, Ringach N et al. Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set. Science 2020;370:eabd5059.

[23] Kelly E, Meng F, Fujita H et al. Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits. Nat Neurosci 2020;23:1102–1110.

[24] Khan AJ, Nair A, Keown CL et al. Cerebro-cerebellar resting-state functional connectivity in children and adolescents with autism spectrum disorder. Biol Psychiatry 2015;78:625–634.

[25] Lai ESK, Nakayama H, Miyazaki T et al. An autism-associated neuroligin-3 mutation affects developmental synapse elimination in the cerebellum. Front Neural Circuits 2021;15:676891.

[26] Leto K, Carletti B, Williams IM et al. Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 2006;26:11682–11694.

[27] Leung C, Cao F, Nguyen R et al. Activation of entorhinal cortical projections to the dentate gyrus underlies social memory retrieval. Cell Rep 2018;23:2379–2391.

[28] Lindeman S, Hong S, Kros L et al. Cerebellar Purkinje cells can differentially modulate coherence between sensory and motor cortex depending on region and behavior. Proc Natl Acad Sci USA 2021;118:e2015292118.

[29] Low AYT, Goldstein N, Gaunt JR et al. Reverse-translational identification of a cerebellar satiation network. Nature 2021;600:269–273.

[30] Ma KY, Cai XY, Wang XT et al. Three-dimensional heterogeneity of cerebellar interposed nucleus-recipient zones in the thalamic nuclei. Neurosci Bull 2021;37:1529–1541.

[31] Madisen L, Zwingman TA, Sunkin SM et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 2010;13:133–140.

[32] Mostofsky SH, Powell SK, Simmonds DJ et al. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain 2009;132:2413–2425.

[33] Peter S, Ten Brinke MM, Stedehouder J et al. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nat Commun 2016;7:12627.

[34] Peter S, De Zeeuw CI, Boeckers TM et al. Cerebellar and striatal pathologies in mouse models of autism spectrum disorder. Adv Anat Embryol Cell Biol 2017;224:103–119.

[35] Pierce K, Haist F, Sedaghat F et al. The brain response to personally familiar faces in autism: findings of fusiform activity and beyond. Brain 2004;127:2703–2716.

[36] Piochon C, Kloth AD, Grasselli G et al. Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 2014;5:5586.

[37] Pisano TJ, Dhanerawala ZM, Kislin M et al. Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain. Cell Rep 2021;36:109721.

[38] Reith RM, McKenna J, Wu H et al. Loss of TsC2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis 2013;51:93–103.

[39] Rothwell PE, Fuccillo MV, Maxeiner S et al. Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 2014;158:198–212.

[40] Sathyanesan A, Zhou J, Scafidi J et al. Emerging connections between cerebellar development, behaviour and complex brain disorders. Nat Rev Neurosci 2019;20:298–313.

[41] Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 2009;44:489–501.

[42] Stoodley CJ, D’Mello AM, Ellegood J et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat Neurosci 2017;20:1744–1751.

[43] Su LD, Xu FX, Wang XT et al. Cerebellar dysfunction, cerebro-cerebellar connectivity and autism spectrum disorders. Neurosci 2020;S0306-4522:30323–30327.

[44] Südhof TC. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell 2017;171:745–769.

[45] Tabuchi K, Blundell J, Etherton MR et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 2007;318:71–76.

[46] Tervo DG, Hwang BY, Viswanathan S et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 2016;92:372–382.

[47] Teune TM, van der Burg J, van der Moer J et al. Topography of cerebellar nuclear projections to the brain stem in the rat. Prog Brain Res 2000;124:141–172.

[48] Tsai PT, Hull C, Chu Y et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 2012;488:647–651.

[49] Tschida K, Michael V, Takatoh J et al. A specialized neural circuit gates social vocalizations in the mouse. Neuron 2019;103:459–472.e4.

[50] Uchigashima M, Cheung A, Futai K. Neuroligin-3: a circuit-specific synapse organizer that shapes normal function and autism spectrum disorder-associated dysfunction. Front Mol Neurosci 2021;14:749164.

[51] Wang SS-H, Kloth AD, Badura A. The cerebellum, sensitive periods, and autism. Neuron 2014;83:518–532.

[52] Wang R, Tan J, Guo J et al. Aberrant development and synaptic transmission of cerebellar cortex in a VPA induced mouse autism model. Front Cell Neurosci 2018;12:500.

[53] Wang X, Chou X, Peng B et al. A cross-modality enhancement of defensive flight via parvalbumin neurons in zona incerta. Elife 2019;8:e42728.

[54] Witter L, Canto CB, Hoogland TM et al. Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation. Front Neural Circuits 2013;7:133.

[55] Xu FX, Wang XT, Cai XY et al. Purkinje cell-specific MeCP2 deficiency leads to motor deficit 1 and autistic-like behavior due to aberrations in PTP1B-TrkB-SK signaling. Cell Rep 2023;42:113559.

[56] Yoshihara Y, Mizuno T, Nakahira M et al. A genetic approach to visualization neurotechnique of multisynaptic neural pathways using plant lectin transgene. Neuron 1999;22:33–41.

[57] Zarate-Lopez D, Torres-Chávez AL, Gálvez-Contreras AY et al. Three decades of valproate: a current model for studying autism spectrum disorder. Curr Neuropharmacol 2024;22:260–289.

[58] Zhang B, Chen LY, Liu X et al. Neuroligins sculpt cerebellar Purkinje-cell circuits by differential control of distinct classes of synapses. Neuron 2015;87:781–796.

[59] Zhou JH, Wang XT, Zhou L et al. Ablation of TFR1 in Purkinje cells inhibits mGlu1 trafficking and impairs motor coordination, but not autistic-like behaviors. J Neurosci 2017;37:11335–11352.

[60] Zingg B, Chou XL, Zhang ZG et al. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron 2017;93:33–47.

RIGHTS & PERMISSIONS

2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.