title: Cerebellar zonal patterning relies on Purkinje cell neurotransmission.
abstract: 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.
authors.affiliation: 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.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: White
authors.affiliation: 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.
authors.forename: Marife
authors.initials: M
authors.lastname: Arancillo
authors.affiliation: 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.
authors.forename: Trace L
authors.initials: TL
authors.lastname: Stay
authors.affiliation: 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.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: George-Jones
authors.affiliation: 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.
authors.forename: Sabrina L
authors.initials: SL
authors.lastname: Levy
authors.affiliation: University of Tennessee Health Science Center, Departments of Anatomy and Neurobiology, Memphis, Tennessee 38163.
authors.forename: Detlef H
authors.initials: DH
authors.lastname: Heck
authors.affiliation: 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 sillitoe@bcm.edu.
authors.forename: Roy V
authors.initials: RV
authors.lastname: Sillitoe
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D009929:Organ Size / Q000235:genetics; D011689:Purkinje Cells / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; C091104:Purkinje cell protein L7; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse
keywords: ataxia; circuitry; connectivity; gene expression; inhibition; physiology