Publications by authors named "Lauren N Miterko"

9 Publications

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Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia.

Nat Commun 2021 02 26;12(1):1295. Epub 2021 Feb 26.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.

Deep brain stimulation (DBS) relieves motor dysfunction in Parkinson's disease, and other movement disorders. Here, we demonstrate the potential benefits of DBS in a model of ataxia by targeting the cerebellum, a major motor center in the brain. We use the Car8 mouse model of hereditary ataxia to test the potential of using cerebellar nuclei DBS plus physical activity to restore movement. While low-frequency cerebellar DBS alone improves Car8 mobility and muscle function, adding skilled exercise to the treatment regimen additionally rescues limb coordination and stepping. Importantly, the gains persist in the absence of further stimulation. Because DBS promotes the most dramatic improvements in mice with early-stage ataxia, we postulated that cerebellar circuit function affects stimulation efficacy. Indeed, genetically eliminating Purkinje cell neurotransmission blocked the ability of DBS to reduce ataxia. These findings may be valuable in devising future DBS strategies.
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http://dx.doi.org/10.1038/s41467-021-21417-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910465PMC
February 2021

cerebellar circuit function is disrupted in an mouse model of Duchenne muscular dystrophy.

Dis Model Mech 2019 12 9;13(2). Epub 2019 Dec 9.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female (also known as ) mice. Purkinje cell simple spike firing rate is significantly lower in mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.040840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906634PMC
December 2019

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

Cerebellum 2019 Dec;18(6):1064-1097

Department of Pathology and Immunology, Department of Neuroscience, Program in Developmental Biology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX, 77030, USA.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.
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http://dx.doi.org/10.1007/s12311-019-01041-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867990PMC
December 2019

Current Opinions and Consensus for Studying Tremor in Animal Models.

Cerebellum 2019 Dec;18(6):1036-1063

Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.
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http://dx.doi.org/10.1007/s12311-019-01037-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872927PMC
December 2019

Persistent motor dysfunction despite homeostatic rescue of cerebellar morphogenesis in the Car8 waddles mutant mouse.

Neural Dev 2019 03 12;14(1). Epub 2019 Mar 12.

Department of Pathology and Immunology, Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX, 77030, USA.

Background: Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8 mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology.

Methods: To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca signaling in Purkinje cells, alters cerebellar development in Car8 mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development.

Results: Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists.

Conclusions: Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.
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http://dx.doi.org/10.1186/s13064-019-0130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417138PMC
March 2019

Shaping Diversity Into the Brain's Form and Function.

Front Neural Circuits 2018 10;12:83. Epub 2018 Oct 10.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States.

The brain contains a large diversity of unique cell types that use specific genetic programs to control development and instruct the intricate wiring of sensory, motor, and cognitive brain regions. In addition to their cellular diversity and specialized connectivity maps, each region's dedicated function is also expressed in their characteristic gross external morphologies. The folds on the surface of the cerebral cortex and cerebellum are classic examples. But, to what extent does structure relate to function and at what spatial scale? We discuss the mechanisms that sculpt functional brain maps and external morphologies. We also contrast the cryptic structural defects in conditions such as autism spectrum disorders to the overt microcephaly after Zika infections, taking into consideration that both diseases disrupt proper cognitive development. The data indicate that dynamic processes shape all brain areas to fit into jigsaw-like patterns. The patterns in each region reflect circuit connectivity, which ultimately supports local signal processing and accomplishes multi-areal integration of information processing to optimize brain functions.
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http://dx.doi.org/10.3389/fncir.2018.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191489PMC
March 2019

Climbing Fiber Development Is Impaired in Postnatal Car8 Mice.

Cerebellum 2018 Feb;17(1):56-61

Department of Pathology and Immunology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX, 77030, USA.

The cerebellum is critical for an array of motor functions. During postnatal development, the Purkinje cells (PCs) guide afferent topography to establish the final circuit. Perturbing PC morphogenesis or activity during development can result in climbing fiber (CF) multi-innervation or mis-patterning. Structural defects during circuit formation typically have long-term effects on behavior as they contribute to the phenotype of movement disorders such as cerebellar ataxia. The Car8 mouse is one model in which early circuit destruction influences movement. However, although the loss of Car8 leads to the mis-wiring of afferent maps and abnormal PC firing, adult PC morphology is largely intact and there is no neurodegeneration. Here, we sought to uncover how defects in afferent connectivity arise in Car8 mutants to resolve how functional deficits persist in motor diseases with subtle neuropathology. To address this problem, we analyzed CF development during the first 3 weeks of life. By immunolabeling CF terminals with VGLUT2, we found evidence of premature CF synapse elimination and delayed translocation from PC somata at postnatal day (P) 10 in Car8 mice. Surprisingly, by P15, the wiring normalized, suggesting that CAR8 regulates the early but not the late stages of CF development. The data support the hypothesis of a defined sequence of events for cerebellar circuits to establish function.
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http://dx.doi.org/10.1007/s12311-017-0886-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053913PMC
February 2018

The pledge, the turn, and the prestige of transient cerebellar alterations in SCA6.

J Physiol 2017 02;595(3):607-608

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA.

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http://dx.doi.org/10.1113/JP273301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285714PMC
February 2017

Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration.

Neurobiol Dis 2016 Feb 14;86:86-98. Epub 2015 Nov 14.

Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Department of Neuroscience, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.

Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca(2+)-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca(2+) influx eliminated ectopic zones. Our findings in Car8(wdl) mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration.
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http://dx.doi.org/10.1016/j.nbd.2015.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778569PMC
February 2016