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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2021)

Bioelectric signaling is evolutionarily conserved and maintained in all living cells through the selective expression of ion channels. In excitable cells like neurons, ion channels play an essential and well characterized role in defining the properties of action potentials. Less is known about their role in non-excitable cells such as neural stem cells and neural progenitor cells. Recent studies in mice have found that the loss of a voltage-gated potassium channel, Kv1.1, leads to a dramatic increase in hippocampal neurons. The hippocampus is critical for learning and memory, and it harbors one of two well-established neurogenic niches in the adult mouse brain. Here, we investigated the role of Kv1.1 in early postnatal and adult hippocampal neurogenesis. In Chapter 2, we first examined the role of Kv1.1 in early postnatal neurogenesis. We found that loss of Kv1.1 depolarizes the membrane potential of neural progenitor cells and increases the proliferation of neural progenitor cells through the TrkB signaling pathway. Next, we assessed the role of Kv1.1 in adult hippocampal neurogenesis in Chapter 3. We observed that conditional deletion of Kv1.1 in adult neural stem cells causes an initial increase in proliferation that eventually depletes the neural stem cell pool. Furthermore, neurons produced from adult neural stem cells lacking Kv1.1 had impaired maturation and positioning. These mice also displayed hippocampal-dependent learning and memory deficits. Together, these findings support an important role for this voltage-gated ion channel in adult neurogenesis. As aberrant neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases, understanding the role of Kv1.1 in adult neurogenesis provides a framework for identifying new therapeutic targets to promote healthy neurogenesis and cognition.

    Cover page: Kv1.1 regulation of adult hippocampal neurogenesis
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2016)
    Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.
      Cover page: Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2016)
      Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.
        Cover page: Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples
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