Publications by authors named "Joshua J White"

21 Publications

  • Page 1 of 1

Region-specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1.

Brain Pathol 2021 Mar 16:e12946. Epub 2021 Mar 16.

Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands.

Purkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties, projection patterns, and susceptibility to disease. In particular, multiple mouse models that feature Purkinje cell degeneration are characterized by incomplete and patterned Purkinje cell degeneration, suggestive of relative sparing of Purkinje cell subpopulations, such as those expressing Aldolase C/zebrinII (AldoC) or residing in the vestibulo-cerebellum. Here, we investigated a well-characterized Purkinje cell-specific mouse model for spinocerebellar ataxia type 1 (SCA1) that expresses human ATXN1 with a polyQ expansion (82Q). Our pathological analysis confirms previous findings that Purkinje cells of the vestibulo-cerebellum, i.e., the flocculonodular lobes, and crus I are relatively spared from key pathological hallmarks: somatodendritic atrophy, and the appearance of p62/SQSTM1-positive inclusions. However, immunohistological analysis of transgene expression revealed that spared Purkinje cells do not express mutant ATXN1 protein, indicating the sparing of Purkinje cells can be explained by an absence of transgene expression. Additionally, we found that Purkinje cells in other cerebellar lobules that typically express AldoC, not only display severe pathology but also show loss of AldoC expression. The relatively preserved flocculonodular lobes and crus I showed a substantial fraction of Purkinje cells that expressed the mutant protein and displayed pathology as well as loss of AldoC expression. Despite considerable pathology in these lobules, behavioral analyses demonstrated a relative sparing of related functions, suggestive of sufficient functional cerebellar reserve. Together, the data indicate that mutant ATXN1 affects both AldoC-positive and AldoC-negative Purkinje cells and disrupts normal parasagittal AldoC expression in Purkinje cells. Our results show that, in a mouse model otherwise characterized by widespread Purkinje cell degeneration, sparing of specific subpopulations is sufficient to maintain normal performance of specific behaviors within the context of the functional, modular map of the cerebellum.
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http://dx.doi.org/10.1111/bpa.12946DOI Listing
March 2021

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

Young man with dysphagia.

J Am Coll Emerg Physicians Open 2021 Feb 5;2(1):e12326. Epub 2020 Dec 5.

Department of Emergency Medicine Pella Regional Health Center Pella Iowa USA.

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http://dx.doi.org/10.1002/emp2.12326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819262PMC
February 2021

Man with nausea, vomiting, and left-sided weakness.

J Am Coll Emerg Physicians Open 2020 Dec 6;1(6):1763-1764. Epub 2020 Nov 6.

Department of Emergency Medicine Pella Regional Health Center Pella Iowa USA.

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http://dx.doi.org/10.1002/emp2.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771733PMC
December 2020

Purkinje cell misfiring generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation.

Elife 2020 03 17;9. Epub 2020 Mar 17.

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

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.
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http://dx.doi.org/10.7554/eLife.51928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077982PMC
March 2020

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

Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells.

Sci Rep 2019 02 11;9(1):1742. Epub 2019 Feb 11.

Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.

Purkinje cells receive synaptic input from several classes of interneurons. Here, we address the roles of inhibitory molecular layer interneurons in establishing Purkinje cell function in vivo. Using conditional genetics approaches in mice, we compare how the lack of stellate cell versus basket cell GABAergic neurotransmission sculpts the firing properties of Purkinje cells. We take advantage of an inducible Ascl1 allele to spatially and temporally target the deletion of the vesicular GABA transporter, Vgat, in developing neurons. Selective depletion of basket cell GABAergic neurotransmission increases the frequency of Purkinje cell simple spike firing and decreases the frequency of complex spike firing in adult behaving mice. In contrast, lack of stellate cell communication increases the regularity of Purkinje cell simple spike firing while increasing the frequency of complex spike firing. Our data uncover complementary roles for molecular layer interneurons in shaping the rate and pattern of Purkinje cell activity in vivo.
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http://dx.doi.org/10.1038/s41598-018-38264-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370775PMC
February 2019

WGA-Alexa Conjugates for Axonal Tracing.

Curr Protoc Neurosci 2017 Apr 10;79:1.28.1-1.28.24. Epub 2017 Apr 10.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.

Anatomical labeling approaches are essential for understanding brain organization. Among these approaches are various methods of performing tract tracing. However, a major hurdle to overcome when marking neurons in vivo is visibility. Poor visibility makes it challenging to image a desired neuronal pathway so that it can be easily differentiated from a closely neighboring pathway. As a result, it becomes impossible to analyze individual projections or their connections. The tracer that is chosen for a given purpose has a major influence on the quality of the tracing. Here, we describe the wheat germ agglutinin (WGA) tracer conjugated to Alexa fluorophores for reliable high-resolution tracing of central nervous system projections. Using the mouse cerebellum as a model system, we implement WGA-Alexa tracing for marking and mapping neural circuits that control motor function. We also show its utility for marking localized regions of the cerebellum after performing single-unit extracellular recordings in vivo. © 2017 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpns.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830103PMC
April 2017

Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice.

Nat Commun 2017 04 4;8:14912. Epub 2017 Apr 4.

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

Theories of cerebellar function place the inferior olive to cerebellum connection at the centre of motor behaviour. One possible implication of this is that disruption of olivocerebellar signalling could play a major role in initiating motor disease. To test this, we devised a mouse genetics approach to silence glutamatergic signalling only at olivocerebellar synapses. The resulting mice had a severe neurological condition that mimicked the early-onset twisting, stiff limbs and tremor that is observed in dystonia, a debilitating movement disease. By blocking olivocerebellar excitatory neurotransmission, we eliminated Purkinje cell complex spikes and induced aberrant cerebellar nuclear activity. Pharmacologically inhibiting the erratic output of the cerebellar nuclei in the mutant mice improved movement. Furthermore, deep brain stimulation directed to the interposed cerebellar nuclei reduced dystonia-like postures in these mice. Collectively, our data uncover a neural mechanism by which olivocerebellar dysfunction promotes motor disease phenotypes and identify the cerebellar nuclei as a therapeutic target for surgical intervention.
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http://dx.doi.org/10.1038/ncomms14912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382291PMC
April 2017

Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models.

Hum Mol Genet 2016 12;25(23):5083-5093

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated in many human diseases, but the in vivo functions of most RBPs and the splicing outcome upon their loss remain largely unexplored. Here we report that constitutive deletion of Rbm17, which encodes an RBP with a putative role in splicing, causes early embryonic lethality in mice and that its loss in Purkinje neurons leads to rapid degeneration. Transcriptome profiling of Rbm17-deficient and control neurons and subsequent splicing analyses using CrypSplice, a new computational method that we developed, revealed that more than half of RBM17-dependent splicing changes are cryptic. Importantly, RBM17 represses cryptic splicing of genes that likely contribute to motor coordination and cell survival. This finding prompted us to re-analyze published datasets from a recent report on TDP-43, an RBP implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as it was demonstrated that TDP-43 represses cryptic exon splicing to promote cell survival. We uncovered a large number of TDP-43-dependent splicing defects that were not previously discovered, revealing that TDP-43 extensively regulates cryptic splicing. Moreover, we found a significant overlap in genes that undergo both RBM17- and TDP-43-dependent cryptic splicing repression, many of which are associated with survival. We propose that repression of cryptic splicing by RBPs is critical for neuronal health and survival. CrypSplice is available at www.liuzlab.org/CrypSplice.
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http://dx.doi.org/10.1093/hmg/ddw337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968355PMC
December 2016

Importance of Both Early Reperfusion and Therapeutic Hypothermia in Limiting Myocardial Infarct Size Post-Cardiac Arrest in a Porcine Model.

JACC Cardiovasc Interv 2016 12 9;9(23):2403-2412. Epub 2016 Nov 9.

University of Arizona Sarver Heart Center, Tucson, Arizona; University of Basel, Basel, Switzerland.

Objectives: The aim of this study was to test the hypothesis that hypothermia and early reperfusion are synergistic for limiting infarct size when an acutely occluded coronary is associated with cardiac arrest.

Background: Cohort studies have shown that 1 in 4 post-cardiac arrest patients without ST-segment elevation has an acutely occluded coronary artery. However, many interventional cardiologists remain unconvinced that immediate coronary angiography is needed in these patients.

Methods: Thirty-two swine (mean weight 35 ± 5 kg) were randomly assigned to 1 of the following 4 treatment groups: group A, hypothermia and reperfusion; group B, hypothermia and no reperfusion; group C, no hypothermia and reperfusion; and group D, no hypothermia and no reperfusion. The left anterior descending coronary artery was occluded with an intracoronary balloon, and ventricular fibrillation was electrically induced. Cardiopulmonary resuscitation was begun after 4 min of cardiac arrest. Defibrillation was attempted after 2 min of cardiopulmonary resuscitation. Resuscitated animals randomized to hypothermia were rapidly cooled to 34°C, whereas those randomized to reperfusion had such after 45 min of left anterior descending coronary artery occlusion.

Results: At 4 h, myocardial infarct size was calculated. Group A had the smallest infarct size at 16.1 ± 19.6% (p < 0.05). Group C had an intermediate infarct size at 29.5 ± 20.2%, whereas groups B and D had the largest infarct sizes at 41.5 ± 15.5% and 41.1 ± 15.0%, respectively.

Conclusions: Acute coronary occlusion is often associated with cardiac arrest, so treatment of resuscitated patients should include early coronary angiography for potential emergent reperfusion, while providing hypothermia for both brain and myocardial protection. Providing only early hypothermia, while delaying coronary angiography, is not optimal.
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http://dx.doi.org/10.1016/j.jcin.2016.08.040DOI Listing
December 2016

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial.

JAMA Psychiatry 2016 Aug;73(8):789-95

Department of Human Development and Family Studies, School of Human Ecology, University of Wisconsin-Madison2Norton School of Family and Consumer Sciences, College of Agriculture, University of Arizona, Tucson5Department of Psychiatry, College of Medicine.

Importance: Limitations of current antidepressants highlight the need to identify novel treatments for major depressive disorder. A prior open trial found that a single session of whole-body hyperthermia (WBH) reduced depressive symptoms; however, the lack of a placebo control raises the possibility that the observed antidepressant effects resulted not from hyperthermia per se, but from nonspecific aspects of the intervention.

Objective: To test whether WBH has specific antidepressant effects when compared with a sham condition and to evaluate the persistence of the antidepressant effects of a single treatment.

Design, Setting, And Participants: A 6-week, randomized, double-blind study conducted between February 2013 and May 2015 at a university-based medical center comparing WBH with a sham condition. All research staff conducting screening and outcome procedures were blinded to randomization status. Of 338 individuals screened, 34 were randomized, 30 received a study intervention, and 29 provided at least 1 postintervention assessment and were included in a modified intent-to-treat efficacy analysis. Participants were medically healthy, aged 18 to 65 years, met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score of 16 or greater.

Interventions: A single session of active WBH vs a sham condition matched for length of WBH that mimicked all aspects of WBH except intense heat.

Main Outcomes And Measures: Between-group differences in postintervention Hamilton Depression Rating Scale scores.

Results: The mean (SD) age was 36.7 (15.2) years in the WBH group and 41.47 (12.54) years in the sham group. Immediately following the intervention, 10 participants (71.4%) randomized to sham treatment believed they had received WBH compared with 15 (93.8%) randomized to WBH. When compared with the sham group, the active WBH group showed significantly reduced Hamilton Depression Rating Scale scores across the 6-week postintervention study period (WBH vs sham; week 1: -6.53, 95% CI, -9.90 to -3.16, P < .001; week 2: -6.35, 95% CI, -9.95 to -2.74, P = .001; week 4: -4.50, 95% CI, -8.17 to -0.84, P = .02; and week 6: -4.27, 95% CI, -7.94 to -0.61, P = .02). These outcomes remained significant after evaluating potential moderating effects of between-group differences in baseline expectancy scores. Adverse events in both groups were generally mild.

Conclusions And Relevance: Whole-body hyperthermia holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT01625546.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.1031DOI Listing
August 2016

An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice.

J Neurosci Methods 2016 Mar 14;262:21-31. Epub 2016 Jan 14.

Department of Pathology and Immunology, Department of Neuroscience, 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. Electronic address:

Background: Electrophysiological recording approaches are essential for understanding brain function. Among these approaches are various methods of performing single-unit recordings. However, a major hurdle to overcome when recording single units in vivo is stability. Poor stability results in a low signal-to-noise ratio, which makes it challenging to isolate neuronal signals. Proper isolation is needed for differentiating a signal from neighboring cells or the noise inherent to electrophysiology. Insufficient isolation makes it impossible to analyze full action potential waveforms. A common source of instability is an inadequate surgery. Problems during surgery cause blood loss, tissue damage and poor healing of the surrounding tissue, limited access to the target brain region, and, importantly, unreliable fixation points for holding the mouse's head.

New Method: We describe an optimized surgical procedure that ensures limited tissue damage and delineate a method for implanting head plates to hold the animal firmly in place.

Results: Using the cerebellum as a model, we implement an extracellular recording technique to acquire single units from Purkinje cells and cerebellar nuclear neurons in behaving mice. We validate the stability of our method by holding single units after injecting the powerful tremorgenic drug harmaline. We performed multiple structural analyses after recording.

Comparison With Existing Methods: Our approach is ideal for studying neuronal function in active mice and valuable for recording single-neuron activity when considerable motion is unavoidable.

Conclusions: The surgical principles we present for accessing the cerebellum can be easily adapted to examine the function of neurons in other brain regions.
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http://dx.doi.org/10.1016/j.jneumeth.2016.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778558PMC
March 2016

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

Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.

Cell 2015 Mar;160(6):1087-98

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative proteinopathy, in which a mutant protein (in this case, ATAXIN1) accumulates in neurons and exerts toxicity; in SCA1, this process causes progressive deterioration of motor coordination. Seeking to understand how post-translational modification of ATAXIN1 levels influences disease, we discovered that the RNA-binding protein PUMILIO1 (PUM1) not only directly regulates ATAXIN1 but also plays an unexpectedly important role in neuronal function. Loss of Pum1 caused progressive motor dysfunction and SCA1-like neurodegeneration with motor impairment, primarily by increasing Ataxin1 levels. Breeding Pum1(+/-) mice to SCA1 mice (Atxn1(154Q/+)) exacerbated disease progression, whereas breeding them to Atxn1(+/-) mice normalized Ataxin1 levels and largely rescued the Pum1(+/-) phenotype. Thus, both increased wild-type ATAXIN1 levels and PUM1 haploinsufficiency could contribute to human neurodegeneration. These results demonstrate the importance of studying post-transcriptional regulation of disease-driving proteins to reveal factors underlying neurodegenerative disease.
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http://dx.doi.org/10.1016/j.cell.2015.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383046PMC
March 2015

In vivo analysis of Purkinje cell firing properties during postnatal mouse development.

J Neurophysiol 2015 Jan 29;113(2):578-91. Epub 2014 Oct 29.

Department of Pathology and Immunology, Department of Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, Houston, Texas

Purkinje cell activity is essential for controlling motor behavior. During motor behavior Purkinje cells fire two types of action potentials: simple spikes that are generated intrinsically and complex spikes that are induced by climbing fiber inputs. Although the functions of these spikes are becoming clear, how they are established is still poorly understood. Here, we used in vivo electrophysiology approaches conducted in anesthetized and awake mice to record Purkinje cell activity starting from the second postnatal week of development through to adulthood. We found that the rate of complex spike firing increases sharply at 3 wk of age whereas the rate of simple spike firing gradually increases until 4 wk of age. We also found that compared with adult, the pattern of simple spike firing during development is more irregular as the cells tend to fire in bursts that are interrupted by long pauses. The regularity in simple spike firing only reached maturity at 4 wk of age. In contrast, the adult complex spike pattern was already evident by the second week of life, remaining consistent across all ages. Analyses of Purkinje cells in alert behaving mice suggested that the adult patterns are attained more than a week after the completion of key morphogenetic processes such as migration, lamination, and foliation. Purkinje cell activity is therefore dynamically sculpted throughout postnatal development, traversing several critical events that are required for circuit formation. Overall, we show that simple spike and complex spike firing develop with unique developmental trajectories.
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http://dx.doi.org/10.1152/jn.00586.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297795PMC
January 2015

Cerebellar zonal patterning relies on Purkinje cell neurotransmission.

J Neurosci 2014 Jun;34(24):8231-45

Departments of Pathology and Immunology and Department of Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, Houston, Texas 77030 and

Cerebellar circuits are patterned into an array of topographic parasagittal domains called zones. The proper connectivity of zones is critical for motor coordination and motor learning, and in several neurological diseases cerebellar circuits degenerate in zonal patterns. Despite recent advances in understanding zone function, we still have a limited understanding of how zones are formed. Here, we focused our attention on Purkinje cells to gain a better understanding of their specific role in establishing zonal circuits. We used conditional mouse genetics to test the hypothesis that Purkinje cell neurotransmission is essential for refining prefunctional developmental zones into sharp functional zones. Our results show that inhibitory synaptic transmission in Purkinje cells is necessary for the precise patterning of Purkinje cell zones and the topographic targeting of mossy fiber afferents. As expected, blocking Purkinje cell neurotransmission caused ataxia. Using in vivo electrophysiology, we demonstrate that loss of Purkinje cell communication altered the firing rate and pattern of their target cerebellar nuclear neurons. Analysis of Purkinje cell complex spike firing revealed that feedback in the cerebellar nuclei to inferior olive to Purkinje cell loop is obstructed. Loss of Purkinje neurotransmission also caused ectopic zonal expression of tyrosine hydroxylase, which is only expressed in adult Purkinje cells when calcium is dysregulated and if excitability is altered. Our results suggest that Purkinje cell inhibitory neurotransmission establishes the functional circuitry of the cerebellum by patterning the molecular zones, fine-tuning afferent circuitry, and shaping neuronal activity.
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http://dx.doi.org/10.1523/JNEUROSCI.0122-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051975PMC
June 2014

Development of the cerebellum: from gene expression patterns to circuit maps.

Wiley Interdiscip Rev Dev Biol 2013 Jan-Feb;2(1):149-64. Epub 2012 May 7.

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.

The internal structure of the cerebellum reflects an intriguing paradox; its cytoarchitecture is relatively simple and repeated throughout, yet the connections between its neurons are wired into a complex array of gene expression domains and functional circuits. The developmental mechanisms that coordinate the establishment of cerebellar structure and circuitry provide a powerful model for understanding how functional brain networks are formed. Two primary germinal zones generate the cells that make up the cerebellum. Each zone expresses a specific set of genes that establish the cell lineages within the cerebellar anlage. Then, cohorts of differentiated projection neurons and interneuron progenitors migrate into the developing cerebellum. Thereafter, a number of remarkable patterning events occur including transformation of the smooth cerebellar surface into an intricately patterned series of folds, formation of three distinct cellular layers, and the demarcation of parasagittal gene expression domains. Together, these structural and molecular organizations are thought to support the proper connectivity between incoming afferent projections and their target cells. After birth, genetic programs and neural activity repattern synaptic connections into topographic neural networks called modules, which are organized around a longitudinal zone plan and are defined by their molecular, anatomic, and functional properties. WIREs Dev Biol 2013, 2:149-164. doi: 10.1002/wdev.65 For further resources related to this article, please visit the WIREs website.
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http://dx.doi.org/10.1002/wdev.65DOI Listing
January 2014

Postnatal development of cerebellar zones revealed by neurofilament heavy chain protein expression.

Front Neuroanat 2013 9;7. Epub 2013 May 9.

Department of Pathology and Immunology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital Houston, TX, USA ; Department of Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital Houston, TX, USA.

The cerebellum is organized into parasagittal zones that control sensory-motor behavior. Although the architecture of adult zones is well understood, very little is known about how zones emerge during development. Understanding the process of zone formation is an essential step toward unraveling how circuits are constructed to support specific behaviors. Therefore, we focused this study on postnatal development to determine the spatial and temporal changes that establish zonal patterns during circuit formation. We used a combination of wholemount and tissue section immunohistochemistry in mice to show that the cytoskeletal protein neurofilament heavy chain (NFH) is a robust marker for postnatal cerebellar zonal patterning. The patterned expression of NFH is initiated shortly after birth, and compared to the domains of several known zonal markers such as zebrin II, HSP25, neurogranin, and phospholipase Cβ4 (PLCβ4), NFH does not exhibit transient expression patterns that are typically remodeled between stages, and the adult zones do not emerge after a period of uniform expression in all lobules. Instead, we found that throughout postnatal development NFH gradually reveals distinct zones in each cerebellar lobule. The boundaries of individual NFH zones sharpen over time, as zones are refined during the second and third weeks after birth. Double labeling with neurogranin and PLCβ4 further revealed that although the postnatal expression of NFH is spatially and temporally unique, its pattern of zones respects a fundamental and well-known molecular topography in the cerebellum. The dynamics of NFH expression support the hypothesis that adult circuits are derived from an embryonic map that is refined into zones during the first 3-weeks of life.
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http://dx.doi.org/10.3389/fnana.2013.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648691PMC
May 2013

Architecture and development of olivocerebellar circuit topography.

Front Neural Circuits 2012 2;6:115. Epub 2013 Jan 2.

Department of Pathology and Immunology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital Houston, TX, USA ; Department of Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital Houston, TX, USA.

The cerebellum has a simple tri-laminar structure that is comprised of relatively few cell types. Yet, its internal micro-circuitry is anatomically, biochemically, and functionally complex. The most striking feature of cerebellar circuit complexity is its compartmentalized topography. Each cell type within the cerebellar cortex is organized into an exquisite map; molecular expression patterns, dendrite projections, and axon terminal fields divide the medial-lateral axis of the cerebellum into topographic sagittal zones. Here, we discuss the mechanisms that establish zones and highlight how gene expression and neural activity contribute to cerebellar pattern formation. We focus on the olivocerebellar system because its developmental mechanisms are becoming clear, its topographic termination patterns are very precise, and its contribution to zonal function is debated. This review deconstructs the architecture and development of the olivocerebellar pathway to provide an update on how brain circuit maps form and function.
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http://dx.doi.org/10.3389/fncir.2012.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534185PMC
January 2013

Wholemount immunohistochemistry for revealing complex brain topography.

J Vis Exp 2012 Apr 5(62):e4042. Epub 2012 Apr 5.

Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, USA.

The repeated and well-understood cellular architecture of the cerebellum make it an ideal model system for exploring brain topography. Underlying its relatively uniform cytoarchitecture is a complex array of parasagittal domains of gene and protein expression. The molecular compartmentalization of the cerebellum is mirrored by the anatomical and functional organization of afferent fibers. To fully appreciate the complexity of cerebellar organization we previously refined a wholemount staining approach for high throughput analysis of patterning defects in the mouse cerebellum. This protocol describes in detail the reagents, tools, and practical steps that are useful to successfully reveal protein expression patterns in the adult mouse cerebellum by using wholemount immunostaining. The steps highlighted here demonstrate the utility of this method using the expression of zebrinII/aldolaseC as an example of how the fine topography of the brain can be revealed in its native three-dimensional conformation. Also described are adaptations to the protocol that allow for the visualization of protein expression in afferent projections and large cerebella for comparative studies of molecular topography. To illustrate these applications, data from afferent staining of the rat cerebellum are included.
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http://dx.doi.org/10.3791/4042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466652PMC
April 2012