Jorge J. Palop-Esteban, PhD

Assistant Professor
Department of Neurology
+1 415 734-2661
Research Description: 

Mechanisms of Network and Interneuron Dysfunction in Alzheimer’s Disease

Our laboratory seeks 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. We are particularly focused on understanding the role of impaired inhibitory interneurons in network hypersynchrony, altered oscillatory brain rhythms, and cognitive dysfunction in AD.

To study these complex diseases, my laboratory primarily uses mouse models that recapitulate key aspects of the cognitive dysfunction and pathology of these conditions to dissect network and circuits mechanisms of brain dysfunction in mouse models of AD. We use electroencephalography (EEG), local field potentials (LFP), and single-unit recordings to assess neuron activity in vivo, optogenetic approaches to modulate interneuron function in vivo, genetic and pharmacological manipulations to manipulate specific pathways in vivo, and behavioral assessment to determine the cognitive consequences of our mechanistic interventions.

Areas de investigation

Network hypersynchrony in AD and related mouse models: We discovered that mouse models of AD (hAPP mice) develop aberrant patterns of neuronal network activity, including epileptiform activity and non-convulsive seizures, that result in profound anatomical and physiological alterations in learning and memory centers (e.g., calbindin depletions). 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, A 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. 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.

Our current short- and long-term research questions include:
• Does epileptiform activity or network hypersynchrony contribute to AD pathology and cognitive dysfunction in AD and related mouse models?
• Do impaired inhibitory interneurons contribute to altered oscillatory activity and network hypersynchrony?
• Can we identify small-molecule Nav1.1 activators to enhance gamma oscillations in vivo?
• Do inhibitory interneuron cell types have altered molecular profile in AD and related mouse models?
• What are the functional alterations of principal and interneuron cell types in vivo at the single-cell level in mouse models of AD?
• Are synaptic depression and aberrant excitatory neuronal activity mechanistically related?
• What are the molecular mechanisms of hAPP/A-induced epileptiform activity and interneuron dysfunction?
• Is hAPP/A part of a homeostatic mechanism controlling neuronal activity, and is it dysregulated in AD?
• Can we restore cognitive function in AD by enhancing interneuron function?

Mentorship Development: 

9/11/20    Mentoring Across Differences

Publications: 

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

Cell reports

Hanson JE, Ma K, Elstrott J, Weber M, Saillet S, Khan AS, Simms J, Liu B, Kim TA, Yu GQ, Chen Y, Wang TM, Jiang Z, Liederer BM, Deshmukh G, Solanoy H, Chan C, Sellers BD, Volgraf M, Schwarz JB, Hackos DH, Weimer RM, Sheng M, Gill TM, Scearce-Levie K, Palop JJ

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Neurobiology of aging

Babiloni C, Blinowska K, Bonanni L, Cichocki A, De Haan W, Del Percio C, Dubois B, Escudero J, Fernández A, Frisoni G, Guntekin B, Hajos M, Hampel H, Ifeachor E, Kilborn K, Kumar S, Johnsen K, Johannsson M, Jeong J, LeBeau F, Lizio R, Lopes da Silva F, Maestú F, McGeown WJ, McKeith I, Moretti DV, Nobili F, Olichney J, Onofrj M, Palop JJ, Rowan M, Stocchi F, Struzik ZM, Tanila H, Teipel S, Taylor JP, Weiergräber M, Yener G, Young-Pearse T, Drinkenburg WH, Randall F

Ovarian Cycle Stages Modulate Alzheimer-Related Cognitive and Brain Network Alterations in Female Mice.

eNeuro

Broestl L, Worden K, Moreno AJ, Davis EJ, Wang D, Garay B, Singh T, Verret L, Palop JJ, Dubal DB

Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease.

Neuron

Martinez-Losa M, Tracy TE, Ma K, Verret L, Clemente-Perez A, Khan AS, Cobos I, Ho K, Gan L, Mucke L, Alvarez-Dolado M, Palop JJ

Epilepsy as a Network Disorder (2): What can we learn from other network disorders such as dementia and schizophrenia, and what are the implications for translational research?

Epilepsy & behavior : E&B

Scharfman HE, Kanner AM, Friedman A, Blümcke I, Crocker CE, Cendes F, Diaz-Arrastia R, Förstl H, Fenton AA, Grace AA, Palop J, Morrison J, Nehlig A, Prasad A, Wilcox KS, Jette N, Pohlmann-Eden B