Jorge Palop, PhD
Assistant Investigator, Gladstone Institute of Neurological Disease

Other Professional Titles

Assistant Professor, Neurology, University of California, San Francisco
Assistant Investigator, Gladstone Institute of Neurological Disease

Phone

(415) 734-2661

Fax

(415) 355-0824

Assistant

Theodora Pak
(415) 734-2513

On The Web

Areas of Investigation

Our laboratory seek to understand the neuronal processes underlying cognitive impairments in neurodegenerative disorders, such as Alzheimer’s disease (AD), and in neuropsychiatric conditions associated with abnormal synchronization of neuronal networks, such as schizophrenia, autism, and epilepsy. We aim to identify molecular, circuit, and network mechanisms of cognitive dysfunction and to develop novel therapeutic approaches to restore brain functions in AD and related disorders. To study these complex diseases, my laboratory primarily uses mouse models that recapitulate key aspects of the cognitive dysfunction and pathology of these conditions. We use in vivo physiology in behaving mice, including electroencephalography (EEG), local field potentials (LFP), and single-unit recordings, optogenetic approaches, genetic and pharmacological manipulations, and behavioral testing to dissect network and circuits mechanisms of brain dysfunction in mouse models of AD.

Lab Focus

Network hypersynchrony in AD and related mouse models: We discovered that aberrant patterns of neuronal network activity result in profound anatomical and physiological alterations of learning and memory centers and may contribute to cognitive deficits in mouse models of AD (hAPP mice). These unexpected findings may be related to the epileptic phenotype of many pedigrees of patients with early-onset familial AD and to the hyperactivation of neuronal networks in patients with sporadic AD and amyloid-positive nondemented subjects. Thus, network abnormalities leading to, or induced by, Aβ accumulation appear to be a relatively early pathogenic event in AD. These results prompted the field to reexamine the effects of abnormal patterns of network activity on cognitive dysfunction in AD. Therefore, we are investigating mechanisms of network hypersynchronization in AD and testing novel therapies to prevent such deficits.
Altered interneuron dysfunction and oscillatory rhythms in cognitive disorders: Inhibitory interneurons regulate oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in AD. We are currently focused on understanding the role of inhibitory interneurons and oscillatory brain rhythms in cognitive functions in health and disease. We discovered that impaired inhibitory interneurons lead to altered oscillatory activity, network hypersynchrony, and cognitive deficits in mouse models of AD. Importantly, cognitive performance in AD mouse models was improved when interneuron-dependent oscillatory brain activity was enhanced by restoration of Nav1.1 levels in endogenous inhibitory interneurons. We are currently profiling inhibitory interneuron cell types in mouse models of AD to identify potential molecular mechanisms of interneuron dysfunction and potential targets of intervention. We are also dissecting the circuit and neuron alterations in behaving mouse models of AD using single-unit recordings and optogenetic approaches. Thus, we are identifying molecular and circuit mechanisms of brain dysfunction and exploring the therapeutic implications of enhancing inhibitory functions and/or restoring oscillatory rhythms in brain disorders associated with abnormal synchronization of neuronal networks, such as AD, schizophrenia, autism, or epilepsy.
Interneuron cell-based therapy in AD and related models: During brain development, embryonic interneuron precursors are generated in the medial ganglionic eminence (MGE) and retain a remarkable capacity for migration and integration in adult host brains, where they fully mature into functional inhibitory interneurons. Thus, MGE, or MGE-like, precursors provide a great opportunity for cell-based therapy in animal models of neurological disorders linked to impaired inhibitory function. We discovered that transplanting Nav1.1-overexpressing, but not wildtype, MGE-derived interneurons enhanced behavior-related modulation of gamma oscillatory activity, reduced network hypersynchrony, and improved cognitive function in hAPP mice. Interestingly, Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice, indicating the key functional role of interneurons and Nav1.1 for cognitive functions. These findings highlight the potential of Nav1.1 and inhibitory interneurons as a therapeutic target in AD and that disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.
Translational focus: We hope to translate our basic research to develop novel treatments. We are evaluating the therapeutic potential of interneuron-based interventions by using cell-based therapy and pharmacology. We established formal partnerships with major pharmaceutical and biotechnology companies to develop compounds or identify targets that enhance interneuron function or restore brain rhythms in models of AD and epilepsy. We are currently developing small molecule Nav1.1 activators that increase Nav1.1 currents and interneuron-dependent gamma oscillations in vitro and in vivo to develop novel therapies for conditions with impaired interneuron function, including AD and Dravet syndrome.

Achievements

Discovered that mouse models of AD (APP mice) develop aberrant patterns of neuronal network activity, including network hypersynchrony, epileptiform activity, and seizures. Hypersynchronization of neuronal networks has been documented by EEG recordings in the most widely used mouse models of AD, including hAPP-J20, APP/PS1dE9, Tg2576, 5xFAD, 3xTg-AD, APP-TTA, and APP23 mice, and humans with AD disease. These observations raise the possibility that aberrant neuronal activity in AD is a primary upstream mechanism of cognitive dysfunction.
Discovered that aberrant patterns of neuronal network activity result in profound anatomical and physiological alterations of learning and memory centers and may contribute to cognitive deficits in humans with AD and related mouse models.
Discovered that deficits in inhibitory interneurons lead to reduced gamma oscillatory activity, network hypersynchrony, and memory deficits in mouse models of AD.
Discovered the molecular mechanism of altered gamma oscillatory activity, which involves decreased levels of the interneuron-predominant voltage-gated sodium channel Nav1.1 subunit. Importantly, restoring Nav1.1 levels enhanced inhibitory cell–dependent gamma oscillatory activity and cognitive performance in hAPP mice, revealing key roles for Nav1.1 and gamma oscillatory activity in cognition.
Discovered that Nav1.1-overexpression, but not wild-type interneuron transplants reduce network and cognitive deficits in mouse models of AD, indicating that molecular optimization of cell transplants is required for therapeutic benefits in AD.

Affiliations

  • Society for Neuroscience

Professional titles

Assistant Professor, Neurology, University of California, San Francisco
Assistant Investigator, Gladstone Institute of Neurological Disease

Education

1994
BS
  • University of Valencia, Spain
1999
MS
  • International University of Andalusia, Spain
2001
PhD
  • "University of Valencia, Spain"

Honors and Awards

2016 UCSF Neuroscience Graduate Program
2016 UCSF Biomedical Sciences Graduate Program
2015 Keynote speaker. 1st National Hispanic Alzheimer’s Conference, San Antonio, November
2014 Reviewing Editor of eNeuro, the new open access online journal of the Society of Neuroscience
2014 NIH – National Institute of Aging – New Investigator R01
2013 Early Career Review program for the National Institutes of Health (NIH)
2013 Alzheimer’s Association, Investigator Initiated Research Grant (IIRG)
2008 S.D. Bechtel Young Investigator Award
2008 Ramón y Cajal Investigator Award from the Spanish Science and Education Ministry
2006 McBean Postdoctoral Fellowship from the Memory and Aging Center, UCSF
2003 C. Lester and Audrey Hogan Fellowship Award
2003 Postdoctoral Fellowship from the Hillblom Center for the Biology of Aging, UCSF
2001 Fulbright Postdoctoral Fellowship
2001 Postdoctoral Fellowship from the Spanish Science and Education Ministry at the Gladstone Institute of Neurological Disease and University of California, San Francisco
1997 Master Fellowship of the International University of Andalucia, Spain
1996 Predoctoral Fellowship from the Spanish Science and Education Ministry, University of Valencia, Department of Cellular Biology, Valencia, Spain