Honors & Awards
Career Advacement Award, Gladstone Institutes (2019)
F31 Predoctoral Fellowship, National Institute of Aging (2018-2019)
Genentech Foundation Fellowship, Genentech Foundation (2017-2018)
Graduate Student of the Year, Gladstone Institute of Neurological Disease (2017)
Young Scientist Award, Alzheimer's Association (2017)
Discovery Fellowship, UCSF (2016-2019)
Graduate Research Fellowship, National Science Foundation (2014-2017)
Bachelor of Science, University of Maryland College Park (2014)
Bachelor of Science, University of Maryland College Park, Biology & Computer Science (2014)
Doctor of Philosophy, University of California San Francisco (2019)
PhD, University of California, San Francisco, Biomedical Sciences (2019)
BS, University of Maryland, College Park, Computer Science (2014)
BS, University of Maryland, College Park, Biological Sciences: Physiology & Neurobiology (2014)
Lisa Giocomo, Postdoctoral Faculty Sponsor
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease.
2019; 14 (1): 24
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.
View details for DOI 10.1186/s13024-019-0324-6
View details for PubMedID 31186040
View details for PubMedCentralID PMC6558779
- Approaching Alzheimer's disease from a network level. Oncotarget 2017; 8 (6): 9003–4
Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.
2016; 90 (4): 740–51
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.
View details for DOI 10.1016/j.neuron.2016.04.009
View details for PubMedID 27161522
View details for PubMedCentralID PMC5097044
Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2016; 41 (3): 716–25
Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring.
View details for DOI 10.1038/npp.2015.197
View details for PubMedID 26189451
View details for PubMedCentralID PMC4707818