TitleNav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsMartinez-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
JournalNeuron
Volume98
Issue1
Pagination75-89.e5
Date Published2018 Apr 04
ISSN1097-4199
Abstract

Inhibitory interneurons regulate the 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 show that Nav1.1-overexpressing, but not wild-type, interneuron transplants derived from the embryonic medial ganglionic eminence (MGE) enhance behavior-dependent gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in human amyloid precursor protein (hAPP)-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.

DOI10.1016/j.neuron.2018.02.029
Alternate JournalNeuron
PubMed ID29551491
PubMed Central IDPMC5886814
Grant ListU54 NS100717 / NS / NINDS NIH HHS / United States
F32 AG043301 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01 NS041787 / NS / NINDS NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
R01 AG047313 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States