Loss of Tsc1 from Striatal Direct Pathway Neurons Impairs Endocannabinoid-LTD and Enhances Motor Routine Learning

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 Aug 11

PMID 34380034

Citations 10

Authors

Katelyn N Benthall

Katherine R Cording

Alexander H C W Agopyan-Miu

Corinna D Wong

Emily Y Chen

Helen S Bateup

Affiliations

Soon will be listed here.

Abstract

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.

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References

Hisaoka T, Komori T, Kitamura T, Morikawa Y . Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice. Sci Rep. 2018; 8(1):1408. PMC: 5780462. DOI: 10.1038/s41598-018-19844-7. View

Yin X, Jones N, Yang J, Asraoui N, Mathieu M, Cai L . Delayed motor learning in a 16p11.2 deletion mouse model of autism is rescued by locus coeruleus activation. Nat Neurosci. 2021; 24(5):646-657. DOI: 10.1038/s41593-021-00815-7. View

Shonesy B, Parrish W, Haddad H, Stephenson J, Baldi R, Bluett R . Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry. 2018; 84(4):304-315. PMC: 6023784. DOI: 10.1016/j.biopsych.2017.11.036. View

Schiffmann S, Vanderhaeghen J . Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J Neurosci. 1993; 13(3):1080-7. PMC: 6576619. View

Kwon C, Luikart B, Powell C, Zhou J, Matheny S, Zhang W . Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006; 50(3):377-88. PMC: 3902853. DOI: 10.1016/j.neuron.2006.03.023. View

Penagarikano O, Abrahams B, Herman E, Winden K, Gdalyahu A, Dong H . Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell. 2011; 147(1):235-46. PMC: 3390029. DOI: 10.1016/j.cell.2011.08.040. View

Platt R, Zhou Y, Slaymaker I, Shetty A, Weisbach N, Kim J . Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep. 2017; 19(2):335-350. PMC: 5455342. DOI: 10.1016/j.celrep.2017.03.052. View

Auerbach B, Osterweil E, Bear M . Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011; 480(7375):63-8. PMC: 3228874. DOI: 10.1038/nature10658. View

Lim J, Gopalappa R, Kim S, Ramakrishna S, Lee M, Kim W . Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. Am J Hum Genet. 2017; 100(3):454-472. PMC: 5339289. DOI: 10.1016/j.ajhg.2017.01.030. View

10.

Tang G, Gudsnuk K, Kuo S, Cotrina M, Rosoklija G, Sosunov A . Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014; 83(5):1131-43. PMC: 4159743. DOI: 10.1016/j.neuron.2014.07.040. View

11.

Heiman M, Kulicke R, Fenster R, Greengard P, Heintz N . Cell type-specific mRNA purification by translating ribosome affinity purification (TRAP). Nat Protoc. 2014; 9(6):1282-91. PMC: 4102313. DOI: 10.1038/nprot.2014.085. View

12.

Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K . Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell. 2009; 137(7):1235-46. PMC: 3710970. DOI: 10.1016/j.cell.2009.04.024. View

13.

Potter W, Basu T, ORiordan K, Kirchner A, Rutecki P, Burger C . Reduced juvenile long-term depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling. PLoS Biol. 2013; 11(8):e1001627. PMC: 3742461. DOI: 10.1371/journal.pbio.1001627. View

14.

Gerfen C, Surmeier D . Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011; 34:441-66. PMC: 3487690. DOI: 10.1146/annurev-neuro-061010-113641. View

15.

Graybiel A, Grafton S . The striatum: where skills and habits meet. Cold Spring Harb Perspect Biol. 2015; 7(8):a021691. PMC: 4526748. DOI: 10.1101/cshperspect.a021691. View

16.

Kravitz A, Freeze B, Parker P, Kay K, Thwin M, Deisseroth K . Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010; 466(7306):622-6. PMC: 3552484. DOI: 10.1038/nature09159. View

17.

Peixoto R, Wang W, Croney D, Kozorovitskiy Y, Sabatini B . Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. Nat Neurosci. 2016; 19(5):716-724. PMC: 4846490. DOI: 10.1038/nn.4260. View

18.

Lee Y, Kim H, Han P . Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors. Exp Neurobiol. 2019; 27(6):539-549. PMC: 6318563. DOI: 10.5607/en.2018.27.6.539. View

19.

Davis P, Peters J, Krueger D, Sahin M . Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism. Neurotherapeutics. 2015; 12(3):572-83. PMC: 4489948. DOI: 10.1007/s13311-015-0359-5. View

20.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View