Silencing the Majority of Cerebellar Granule Cells Uncovers Their Essential Role in Motor Learning and Consolidation

Galliano, Elisa; Gao, Zhenyu; Schonewille, Martijn; Todorov, Boyan; Simons, Esther; Pop, Andreea; D’Angelo, Egidio; Maagdenberg, Arn M. J. M. van den; Hoebeek, Freek E.; Zeeuw, Chris I. De

doi:10.1016/j.celrep.2013.03.023

Cited by 145 publications

(163 citation statements)

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“…cause ataxia (De Zeeuw et al, 1998;Wulff et al, 2009;Galliano et al, 2013). We investigated behavior of mice that have impaired neurotransmission at the PF to PC synapse (less-excit mutants) or at the molecular layer interneuron to PC synapse (no-inhib mutants), or that suffer from impaired intrinsic plasticity and long-term potentiation (no-LTP mutants) or long-term depression (no-LTD mutants) at the PF to PC synapse.…”

Section: Discussionmentioning

confidence: 99%

“…Together with the swimming behavior analysis in the watermaze test, these data indicate that the specific genetic perturbations had little or no effect on the animals' ability to walk and explore a novel arena, despite consistent impairments in their fine motor coordination as expected from cerebellar-targeting mutations (De Zeeuw et al, 1998;Wulff et al, 2009;Galliano et al, 2013).…”

Section: Cerebellar Mutants Did Not Show Gross Motor Impairment In Opmentioning

confidence: 99%

“…Given the evidence of a plausible cerebellar contribution to the autism-spectrum symptoms described in humans (Courchesne, 1997;Critchley et al, 2000;Garrard et al, 2008), we tested the social behavior of our mice. During the first phase of the experiment (called sociability; Fig.…”

Section: Cerebellar Mutants Did Not Show a Phenotype In Social Behaviormentioning

confidence: 99%

“…• Knock-out mice in which 70 -80% of granule cells (GCs) are silent (called ␣6-Cacna1a or here referred to as less-excit) due to the selective elimination of their P/Q-type Ca 2ϩ -channels, which mediate the bulk of neurotransmitter release at the PF-PC synapse (Galliano et al, 2013).…”

Section: Animalsmentioning

confidence: 99%

“…In two mouse lines, basic neurotransmission onto PCs was impaired: the ␣6-Cacna1a KO, in which PCs lost 70 -80% of their excitatory input from granule cells (referred to as "less-excit"; see Fig. 1; Galliano et al, 2013), and the L7-␥2, in which PCs receive no synaptic inhibitory input from molecular layer interneurons (re- . Subsequently, with no delay, the Social recognition phase (5 min long) started: a second unknown mouse (Stranger 2) was places in the empty compartment.…”

Section: Introductionmentioning

confidence: 99%

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Synaptic Transmission and Plasticity at Inputs to Murine Cerebellar Purkinje Cells Are Largely Dispensable for Standard Nonmotor Tasks

Galliano¹,

Potters²,

Elgersma³

et al. 2013

Journal of Neuroscience

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In addition to its well established role in motor coordination, the cerebellum has been hypothesized to be involved in the control of cognitive and emotional functions. Although a cerebellar contribution to nonmotor functions has been supported by recent studies in human and monkey, it remains to be clarified with an in-depth, systematic approach in mouse mutants. Here we subjected four different cerebellar cell-specific mouse lines whereby the excitatory or inhibitory input to Purkinje cells (PCs) and/or PC postsynaptic plasticity were compromised, to a wide battery of standard cognitive and emotional tests. The four lines, which have all been shown to suffer from impaired motor learning without being ataxic, were tested for social behavior using a sociability task, for spatial navigation using the Morris watermaze, for fear responses using contextual and cued conditioning, and general anxiety using the open-field task. None of the four cerebellum-specific genetic perturbations showed significantly impaired cognitive or emotional behavior. In fact, even without correction for multiple comparisons, only 5 of 154 statistical comparisons showed a marginally significant deficit. Therefore, our data indicate that none of the perturbations of cerebellar functioning studied here affected the cognitive or emotional tests we used. This suggests that there may be a differential impact of the murine and human cerebellum on nonmotor functions. We hypothesize that these differences could be a consequence of the remarkable enlargement of the cerebellar hemispheres during the latest phase of vertebrate phylogeny, which occurred in parallel with the evolution of the cerebral cortex.

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Section: Discussionmentioning

confidence: 99%

Section: Cerebellar Mutants Did Not Show Gross Motor Impairment In Opmentioning

confidence: 99%

Section: Cerebellar Mutants Did Not Show a Phenotype In Social Behaviormentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synaptic Transmission and Plasticity at Inputs to Murine Cerebellar Purkinje Cells Are Largely Dispensable for Standard Nonmotor Tasks

Galliano¹,

Potters²,

Elgersma³

et al. 2013

Journal of Neuroscience

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Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice

Hull,

Wang,

Burns

et al. 2023

Glia

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Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative N‐acetyl‐L‐aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA‐deficient CD mice (Aspanur7/nur7) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l (N‐acetyltransferase‐8‐like, “Nat8l ASO”) that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia‐neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.

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A Guide to In Vivo Optogenetic Applications for Cerebellar Studies

Rooda

Hoebeek

2017

Neuromethods

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Silencing the Majority of Cerebellar Granule Cells Uncovers Their Essential Role in Motor Learning and Consolidation

Cited by 145 publications

References 53 publications

Synaptic Transmission and Plasticity at Inputs to Murine Cerebellar Purkinje Cells Are Largely Dispensable for Standard Nonmotor Tasks

Synaptic Transmission and Plasticity at Inputs to Murine Cerebellar Purkinje Cells Are Largely Dispensable for Standard Nonmotor Tasks

Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice

A Guide to In Vivo Optogenetic Applications for Cerebellar Studies

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