Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease

Guo, Lili; Xiong, Huan; Kim, Jae‐Ick; Wu, Yu-Wei; Lalchandani, Rupa R.; Cui, Yuting; Shu, Yu; Xu, Tonghui; Ding, Jun

doi:10.1038/nn.4082

Cited by 158 publications

(167 citation statements)

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“…Ca 2+ -imaging was performed with a custom-built laser-scanning system based on an Olympus BX61WI microscope (Guo et al, 2015). Two-photon excitation was achieved with a mode-locked Ti:S laser (Chameleon Vision II, Coherent) running at a wavelength of 830 nm (repetition rate: 80 MHz; pulse width: 140 fs).…”

Section: Star Methodsmentioning

confidence: 99%

Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins

Chen

Jiang

Zhang

et al. 2017

Neuron

201

256

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Neurexins are recognized as key organizers of synapses that are essential for normal brain function. However, it is unclear whether neurexins are fundamental building blocks of all synapses with similar overall functions, or context-dependent specifiers of synapse properties. To address this question, we produced triple conditional knockout mice that allow ablating all neurexin transcripts in mice. Using neuron-specific manipulations combined with immunocytochemistry, paired-recordings, and two-photon Ca2+-imaging, we analyzed excitatory synapses formed by climbing fibers on Purkinje cells in cerebellum, and inhibitory synapses formed by parvalbumin- or by somatostatin-positive interneurons on pyramidal layer 5 neurons in the medial prefrontal cortex. After pan-neurexin deletions, we observed in these synapses severe but dramatically different phenotypes that ranged from major impairments in their distribution and function (climbing-fiber synapses) to large decreases in synapse numbers (parvalbumin-positive synapses) and severe alterations in action-potential-induced presynaptic Ca2+-transients (somatostatin-positive synapses). Thus, neurexins primarily function as context-dependent specifiers of synapses.

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Section: Star Methodsmentioning

confidence: 99%

Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins

Chen

Jiang

Zhang

et al. 2017

Neuron

201

256

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“…Dopaminergic projections from the ventral tegmental area are present in the motor cortex, and ablation of dopaminergic terminals in the motor cortex impaired the learning of a reaching task (Hosp et al, 2011). A subsequent study revealed D2-type dopamine receptors mediate spine addition in the motor cortex (Guo et al, 2015). The information conveyed by dopaminergic input to the motor cortex during learning is still unclear; dopamine could be actively selecting rewarding pathways, analogous to striatum, but it is also possible that it simply functions as a permissive factor for normal plasticity.…”

Section: Motor Skill Learningmentioning

confidence: 99%

Circuit Mechanisms of Sensorimotor Learning

Makino

Hwang

Hedrick

et al. 2016

Neuron

193

152

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SUMMARY The relationship between the brain and the environment is flexible, forming the foundation for our ability to learn. Here we review the current state of our understanding of the modifications in the sensorimotor pathway related to sensorimotor learning. We divide the process in three hierarchical levels with distinct goals: 1) sensory perceptual learning, 2) sensorimotor associative learning, and 3) motor skill learning. Perceptual learning optimizes the representations of important sensory stimuli. Associative learning and the initial phase of motor skill learning are ensured by feedback-based mechanisms that permit trial-and-error learning. The later phase of motor skill learning may primarily involve feedback-independent mechanisms operating under the classic Hebbian rule. With these changes under distinct constraints and mechanisms, sensorimotor learning establishes dedicated circuitry for the reproduction of stereotyped neural activity patterns and behavior.

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“…Thus, sensitive in vivo methods are required to investigate the process of synaptic remodeling in PD motor cortex to provide a more complete understand of the pathological progression. Using 2‐photon in vivo imaging microscopy the Ding laboratory and Xu laboratory uncovered abnormal remodeling of neuronal circuits in the motor cortex in various mouse models of PD . The researchers used transcranial, 2‐photon laser scanning microscopy to study the synaptic remodeling of layer V pyramidal neurons in the motor cortex (Fig.…”

Section: Dopamine Regulates Synaptic Plasticity In Motor Cortexmentioning

confidence: 99%

Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex

Wang

Lalchandani

et al. 2017

Movement Disorders

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In Parkinson's disease (PD), dopamine depletion causes dramatic changes in the brain resulting in debilitating cognitive and motor deficits. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time point of PD progression. Models of PD where dopamine tone in the brain are chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this paper, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo, time-lapse imaging and motor-skill behavior assays. In combination with previous studies, a role of the motor cortex in skill-learning, and the impairment of this ability with the loss of dopamine, is becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in the motor-skill learning and cognitive impairments of PD, with the possibility of targeting the motor cortex for future PD therapeutics.Parkinson disease (PD) is a chronic, disabling neurological disease that affected over 4 million people worldwide over the age of 50 in 2005, and is expected double by 2030 1,2,3 . In addition to motor deficits, cognitive deficits, including the impairment of motor skilllearning, are frequent comorbidities in PD: nearly 80% of PD patients eventually develop 4,5 . Progressive degeneration of nigrostriatal dopaminergic neurons is the pathophysiological hallmark of PD, resulting in dramatically reduced dopamine tone in the brains of PD patients 6,7,8 . HHS Public AccessThe most well documented disruption of neural circuitry in PD occurs in the basal ganglia, a composite of several brain structures densely innervated by the dopaminergic system 9 . It is widely accepted that dysfunction of basal ganglia circuitry via the basal ganglia-thalamocortical pathway is responsible for the development of the motor movement disorders observed in PD: the loss of dopaminergic neurons results in excessive activation of the basal ganglia output nuclei and subsequent inhibition of thalamocortical and brainstem motor systems. Therefore, the loss of nigrostriatal dopamine tone is what is thought to ultimately result in the motor dysfunctions observed in PD 10,11 .The neuropathology of PD has been documented principally and extensively through postmortem examination, providing a detailed snapshot of a PD brain at a single time point 12,13 . While much has been discovered regarding the cause of movement disorders in PD, there is little information about the cognitive and skill-learning deficits also present in PD patients. Recent studies have co...

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Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease

Cited by 158 publications

References 50 publications

Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins

Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins

Circuit Mechanisms of Sensorimotor Learning

Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex

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