Delayed motor learning in a 16p11.2 deletion mouse model of autism is rescued by locus coeruleus activation

Yin, Xuming; Jones, N; Yang, Jungwoo; Asraoui, Nabil; Mathieu, Marie‐Eve; Cai, Liwen; Chen, Simon X

doi:10.1038/s41593-021-00815-7

Cited by 24 publications

(17 citation statements)

References 55 publications

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“…Performance in the accelerating rotarod is commonly affected in mice with mutations in ASD-risk genes, as several other genetic ASD mouse models exhibit enhanced rotarod performance ( Kwon et al, 2006 ; Rothwell et al, 2014 ; Nakatani et al, 2009 ; Peñagarikano et al, 2011 ; Platt et al, 2017 ; Chadman et al, 2008 ; Hisaoka et al, 2018 ). However, this is not the case for all ASD-risk genes ( Wang et al, 2016 ; Portmann et al, 2014 ; Yin et al, 2021 ). Most of the aforementioned mouse models have global gene deletions in which brain regions and circuits outside of the striatum could contribute to the phenotype.…”

Section: Discussionmentioning

confidence: 97%

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

et al. 2021

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SUMMARY 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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Section: Discussionmentioning

confidence: 97%

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

et al. 2021

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“…For example, under conditions requiring rapid, forceful yet precise movement, output from the LC-NE system may be required to optimize operations at cellular, circuit and network levels, thereby improving the flow of information through the motor network and ultimately facilitating the execution of reflexive and goal-directed motor behavior. Ample evidence also implicates the LC-NE system in motor dysfunction ( Feeney et al, 1993 ; Von Coelln et al, 2004 ; Rommelfanger et al, 2007 ; Rommelfanger and Weinshenker, 2007 ; Vazey and Aston-Jones, 2012 ; Liu et al, 2013 ; Osier and Dixon, 2016 ; Vermeiren and Deyn, 2017 ; McPherson et al, 2018 ; Sternberg and Schaller, 2019 ; Yin et al, 2021 ). Nevertheless, the details of LC-interactions with CNS motor centers and subsequent influences on motor behavior are lacking.…”

Section: Overviewmentioning

confidence: 99%

Probing the structure and function of locus coeruleus projections to CNS motor centers

Waterhouse

Predale

Plummer

et al. 2022

Front. Neural Circuits

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The brainstem nucleus locus coeruleus (LC) sends projections to the forebrain, brainstem, cerebellum and spinal cord and is a source of the neurotransmitter norepinephrine (NE) in these areas. For more than 50 years, LC was considered to be homogeneous in structure and function such that NE would be released uniformly and act simultaneously on the cells and circuits that receive LC projections. However, recent studies have provided evidence that LC is modular in design, with segregated output channels and the potential for differential release and action of NE in its projection fields. These new findings have prompted a radical shift in our thinking about LC operations and demand revision of theoretical constructs regarding impact of the LC-NE system on behavioral outcomes in health and disease. Within this context, a major gap in our knowledge is the relationship between the LC-NE system and CNS motor control centers. While we know much about the organization of the LC-NE system with respect to sensory and cognitive circuitries and the impact of LC output on sensory guided behaviors and executive function, much less is known about the role of the LC-NE pathway in motor network operations and movement control. As a starting point for closing this gap in understanding, we propose using an intersectional recombinase-based viral-genetic strategy TrAC (Tracing Axon Collaterals) as well as established ex vivo electrophysiological assays to characterize efferent connectivity and physiological attributes of mouse LC-motor network projection neurons. The novel hypothesis to be tested is that LC cells with projections to CNS motor centers are scattered throughout the rostral-caudal extent of the nucleus but collectively display a common set of electrophysiological properties. Additionally, we expect to find these LC projection neurons maintain an organized network of axon collaterals capable of supporting selective, synchronous release of NE in motor circuitries for the purpose of coordinately regulating operations across networks that are responsible for balance and movement dynamics. Investigation of this hypothesis will advance our knowledge of the role of the LC-NE system in motor control and provide a basis for treating movement disorders resulting from disease, injury, or normal aging.

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“…DLS lesions or silencing SPNs impairs learned motor behaviors, and blocking SPN plasticity by deleting NMDA receptors on SPNs prevents mice from learning new motor skills (Dang et al, 2006;Santos et al, 2015;Sheng et al, 2019). Importantly, in psychogenic movement disorders, such as Parkinson's disease, autism spectrum disorders, and L-DOPA-induced dyskinesia, disruption of ensemble activity of neurons in the DLS or M1 may mediate behavioral deficits (Parker et al, 2018;Maltese et al, 2021;Yin et al, 2021). Conversely, neuronal engrams that are not present in the normal brain are formed in the striatum during maladaptive motor behaviors (Girasole et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

Hwang

Roth

et al. 2022

Neuron

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Delayed motor learning in a 16p11.2 deletion mouse model of autism is rescued by locus coeruleus activation

Cited by 24 publications

References 55 publications

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Probing the structure and function of locus coeruleus projections to CNS motor centers

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

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