Shared and specific signatures of locomotor ataxia in mutant mice

Machado, Ana S; Marques, Hugo Gravato; Duarte, Diogo F; Darmohray, Dana M; Carey, Megan R.

doi:10.1101/2020.01.21.914077

Cited by 12 publications

(32 citation statements)

References 64 publications

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“…( D–F ) Same as ( A–C ) but for granule-cell-specific CB1KO mice (N = 4; cyan) and their littermate controls (N = 6; black/gray). See Methods and ( Machado et al, 2015 ; Machado et al, 2020 ) for detailed gait parameter descriptions. …”

Section: Resultsmentioning

confidence: 99%

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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Albergaria

Silva

Darmohray

et al. 2020

eLife

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Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.

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Section: Resultsmentioning

confidence: 99%

“…Mice with cerebellar ataxia show sig. differences variability, interlimb and body coordination ( Machado et al, 2015 ; Machado et al, 2020 ). Global CB1KO mice showed sig.…”

Section: Resultsmentioning

confidence: 99%

Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Albergaria

Silva

Darmohray

et al. 2020

eLife

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“…Notably, none of these locomotor differences were observed in G6KO mice ( Figure 4 -figure supplement 1D-F, Figure 4 -figure supplement 2). Further, these differences do not match the pattern of deficits found in mouse models of cerebellar ataxia ( Figure 4 -figure supplement 2; Lalonde and Strazielle 2007;Machado et al, 2015;Vinueza-Veloz et al, 2015;Machado et al, 2020).…”

Section: Cb1rs Are Dispensable For Locomotor Learningmentioning

confidence: 90%

“…They are not overtly ataxic (Movie 1) and show normal rotarod performance at the ages tested here (Zimmer et al, 1999;Bilkei-Gorzo et al 2005;Kishimoto and Kano 2006). However, since global CB1KOs are hypoactive, and since split-belt treadmill adaptation involves learned changes in interlimb coordination, we first performed a detailed analysis of locomotor kinematics during overground walking (Machado et al 2015, Machado et al 2020 to detect any potential subtle locomotor impairments in CB1KOs (Movie 1).…”

Section: Cb1rs Are Dispensable For Locomotor Learningmentioning

confidence: 99%

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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Albergaria

Silva

Darmohray

et al. 2019

Preprint

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Attempts to identify cellular mechanisms underlying learning often include knocking out genes involved in candidate forms of synaptic plasticity and assessing subsequent effects on behavior. Within the cerebellum, multiple plasticity mechanisms have been proposed as cellular substrates of learning. For example, type 1-cannabinoid receptors (CB1Rs) mediate several forms of synaptic plasticity in the cerebellar cortex and have been implicated in cerebellum-dependent delay eyeblink conditioning in knockout experiments. However, recent work has shown that eyeblink conditioning is modulated by behavioral state, and global CB1KO mice are known to be hypoactive. We therefore asked to what extent altered locomotor activity vs. impaired CB1-dependent plasticity within the cerebellar cortex contribute to learning impairments in these mice. We find that eyeblink conditioning deficits in global CB1KOs can be fully accounted for by their hypoactivity. Impairments disappear when the level of locomotor activity is taken into account, and externally controlling running speed rescues learning. Moreover, both global and cerebellar granule cell-specific CB1KOs exhibit normal cerebellum-dependent locomotor adaptation. Our results suggest that the apparent effects of CB1R deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of hypoactivity. These findings highlight the importance of considering general changes in behavioral state as a powerful means through which individual genes contribute to complex behaviors, particularly in transgenic models.

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Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

Serra

Manusama

Kaiser

et al. 2021

Brain, Behavior, & Immunity - Health

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The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δ E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δ E1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

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Shared and specific signatures of locomotor ataxia in mutant mice

Cited by 12 publications

References 64 publications

Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

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