Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease
Keran Ma,1,2,8 Tara E. Tracy,1,2,8 Magdalena Martinez-Losa,1,2,3,8 Laure Verret,1,2,7 Alexandra Clemente-Perez,1,4 Abdullah S. Khan,1 Inma Cobos,1,5 Kaitlyn Ho,1 Li Gan,1,2,4 Lennart Mucke,1,2,4 Manuel Alvarez-Dolado,1,3,6* and Jorge J. Palop1,2,4 1Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA; 2Department of Neurology, University of California, San Francisco, CA, 94158, USA; 3Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, CSIC, Seville, 41092, Spain; 4Neuroscience Graduate Program, University of California, CA, 94158, USA; 5Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA; 6University Pablo de Olavide, Seville, 41013, Spain; 7Present address: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France 8These authors contributed equally
Inhibitory interneurons regulate oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in Alzheimer's disease (AD). Network dysrhythmias in AD and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons. We hypothesize that using cell-therapy to transplant inhibitory interneurons in the brain would enhance interneuron function and help to coordinate neuronal network activity to improve cognitive function. We found that Nav1.1-overexpressing, but not wild-type, interneuron transplants derived from the embryonic medial ganglionic eminence enhance behavior-dependent gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in human amyloid precursor protein transgenic mice, which simulate key aspects of AD. Increased Nav1.1 levels accelerated action potential kinetics of transplanted fast-spiking and non-fast-spiking interneurons. Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice. We conclude that the efficacy of interneuron transplantation and the function of transplanted cells in an AD-relevant context depend on their Nav1.1 levels. Disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.