About

Diane M. Papazian is a Professor in the Department of Physiology at UCLA and a member of the Brain Research Institute, as well as the Cell & Developmental Biology area within the Graduate Programs in Bioscience. Her research focuses on voltage-gated potassium channels, particularly how these channels open in response to depolarization of the transmembrane voltage and their role in controlling nerve and muscle excitability. Her current projects investigate how voltage controls the activity of Kv3.3 channels and how mutations in these channels cause Spinocerebellar Ataxia Type 13 (SCA13), a human disease characterized by loss of cerebellar neurons and motor problems. SCA13 manifests in two forms: an early-onset neurodevelopmental form and a progressive neurodegenerative form of aging. Her work includes developing zebrafish models to study the effects of disease-causing mutations on neuronal development and function, utilizing techniques from biochemistry, electrophysiology, molecular biology, cell biology, and genetics.

Research topics

• Biology
• Neuroscience
• Genetics

Selected publications

• Altered closed state inactivation gating in Kv4.2 channels results in developmental and epileptic encephalopathies in human patients

  Human Mutation · 2022 · 5 citations

  Senior authorCorresponding
  • Biology
  • Neuroscience
  • Genetics

  channels in normal brain development and function.

  PublisherDOI

• Author response: Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

  2020-07-03

  peer-reviewOpen accessSenior author

  Electrophysiological analysis and imaging in live zebrafish reveal that infant- and adult-onset SCA13 mutations have distinct effects on the electrical activity, development, and survival of cerebellar Purkinje cells.

  PublisherDOI

• Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

  eLife · 2020 · 16 citations

  Senior authorCorresponding
  • Biology
  • Neuroscience

  channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid cell death during cerebellar development. Reducing excitability increased early Purkinje cell survival. In contrast, an adult-onset mutation did not significantly alter basal tonic firing in Purkinje cells, but reduced excitability during evoked high frequency spiking. Purkinje cells expressing the adult-onset mutation matured normally and did not degenerate during cerebellar development. Our results suggest that differential changes in the excitability of cerebellar neurons contribute to the distinct ages of onset and timing of cerebellar degeneration in infant- and adult-onset SCA13.

  PublisherDOI

• Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

  Proceedings of the National Academy of Sciences · 2018-03-26 · 46 citations

  articleOpen accessSenior author

  influx into dendrites and regulating spike timing-dependent plasticity. Here, we show that the V404M mutation specifically affects the mechanism of CSI, enhancing the inactivation of channels that have not opened while dramatically impairing the inactivation of channels that have opened. The mutation gives rise to these opposing effects by increasing the stability of the inactivated state and in parallel, profoundly slowing the closure of open channels, which according to our data, is required for CSI. The larger volume of methionine compared with valine is a major factor underlying altered inactivation gating. Our results suggest that V404M increases the strength of the physical interaction between the pore gate and the voltage sensor regardless of whether the gate is open or closed. Furthermore, in contrast to previous proposals, our data strongly suggest that physical coupling between the voltage sensor and the pore gate is maintained in the inactivated state. The state-dependent effects of V404M on CSI are expected to disturb the regulation of neuronal excitability and the induction of spike timing-dependent plasticity. Our results strongly support a role for altered CSI gating in the etiology of epilepsy and autism in the affected twins.

  PublisherOA PDFDOI

• In Vivo Analysis of Potassium Channelopathies: Loose Patch Recording of Purkinje Cell Firing in Living, Awake Zebrafish

  Methods in molecular biology · 2017-10-20 · 3 citations

  articleSenior author
  PublisherDOI

• Extracellular Loose-Patch Recording of Purkinje Cell Activity in Awake Zebrafish and Emergence of Functional Cerebellar Circuit

  Neuromethods · 2017-12-15 · 3 citations

  book-chapterSenior authorCorresponding
  PublisherDOI

• Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner

  Cellular and Molecular Life Sciences · 2015-04-08 · 32 citations

  articleOpen access

  The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.

  PublisherOA PDFDOI

• Rapid development of Purkinje cell excitability, functional cerebellar circuit, and afferent sensory input to cerebellum in zebrafish

  Frontiers in Neural Circuits · 2014-12-19 · 40 citations

  articleOpen accessSenior authorCorresponding

  The zebrafish has significant advantages for studying the morphological development of the brain. However, little is known about the functional development of the zebrafish brain. We used patch clamp electrophysiology in live animals to investigate the emergence of excitability in cerebellar Purkinje cells, functional maturation of the cerebellar circuit, and establishment of sensory input to the cerebellum. Purkinje cells are born at 3 days post-fertilization (dpf). By 4 dpf, Purkinje cells spontaneously fired action potentials in an irregular pattern. By 5 dpf, the frequency and regularity of tonic firing had increased significantly and most cells fired complex spikes in response to climbing fiber activation. Our data suggest that, as in mammals, Purkinje cells are initially innervated by multiple climbing fibers that are winnowed to a single input. To probe the development of functional sensory input to the cerebellum, we investigated the response of Purkinje cells to a visual stimulus consisting of a rapid change in light intensity. At 4 dpf, sudden darkness increased the rate of tonic firing, suggesting that afferent pathways carrying visual information are already active by this stage. By 5 dpf, visual stimuli also activated climbing fibers, increasing the frequency of complex spiking. Our results indicate that the electrical properties of zebrafish and mammalian Purkinje cells are highly conserved and suggest that the same ion channels, Nav1.6 and Kv3.3, underlie spontaneous pacemaking activity. Interestingly, functional development of the cerebellum is temporally correlated with the emergence of complex, visually-guided behaviors such as prey capture. Because of the rapid formation of an electrically-active cerebellum, optical transparency, and ease of genetic manipulation, the zebrafish has great potential for functionally mapping cerebellar afferent and efferent pathways and for investigating cerebellar control of motor behavior.

  PublisherOA PDFDOI

• Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation

  Human Molecular Genetics · 2014-02-05 · 121 citations

  articleOpen access

  Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A de novo variant was identified in the KCND2 gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current (ISA) channels. The de novo mutation p.Val404Met is novel and occurs at a highly conserved residue within the C-terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form ISA channels in vivo. Discovery of a functionally relevant novel de novo variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports KCND2 as the causal gene for epilepsy in this family. Interaction of KCND2 with other genes implicated in autism and the role of KCND2 in synaptic plasticity provide suggestive evidence of an etiological role in autism.

  PublisherOA PDFDOI

• Kcnd2 Mutation Associated with Autism and Epilepsy Impairs Inactivation Gating in Kv4.2 K+ Channels

  Biophysical Journal · 2014-01-01 · 2 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM043459

  NIH · $6.0M · 2015

• NIH Grant R01GM066686

  NIH · $1.3M · 2006

• NIH Grant R01NS058500

  NIH · $1.3M · 2012

Frequent coauthors

• Lily Yeh Jan

  University of California, San Francisco

  35 shared

• Yuh Nung Jan

  University of California, San Francisco

  30 shared

• Thomas L. Schwarz

  24 shared

• Leslie C. Timpe

  San Francisco State University

  21 shared

• Meng‐Chin Lin

  University of California, Los Angeles

  20 shared

• Bruce L. Tempel

  University of Washington

  15 shared

• Allan F. Mock

  University of California, Los Angeles

  15 shared

• Jui-Yi Hsieh

  12 shared

Labs

• Diane M. Papazian LabPI

Awards & honors

• Suzanne Eaton, Ph.D. Memorial Prize
• Taylor M. Brown Memorial Award
• Asrican Sophie & Jack Award