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

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2018 Mar 20

PMID 29551491

Citations 109

Authors

Magdalena Martinez-Losa

Tara E Tracy

Keran Ma

Laure Verret

Alexandra Clemente-Perez

Abdullah S Khan

Inma Cobos

Kaitlyn Ho

Li Gan

Lennart Mucke

Manuel Alvarez-Dolado

Jorge J Palop

Affiliations

Soon will be listed here.

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.

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References

Busche M, Kekus M, Adelsberger H, Noda T, Forstl H, Nelken I . Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat Neurosci. 2015; 18(11):1623-30. DOI: 10.1038/nn.4137. View

Rubio S, Vega-Flores G, Martinez A, Bosch C, Perez-Mediavilla A, Del Rio J . Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease. FASEB J. 2012; 26(11):4458-67. DOI: 10.1096/fj.12-208413. View

Busche M, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold K, Haass C . Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science. 2008; 321(5896):1686-9. DOI: 10.1126/science.1162844. View

Yamamoto K, Tanei Z, Hashimoto T, Wakabayashi T, Okuno H, Naka Y . Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 2015; 11(6):859-865. DOI: 10.1016/j.celrep.2015.04.017. View

Kim D, Carey B, Wang H, Ingano L, Binshtok A, Wertz M . BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007; 9(7):755-64. PMC: 2747787. DOI: 10.1038/ncb1602. View

Liu Y, Weick J, Liu H, Krencik R, Zhang X, Ma L . Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol. 2013; 31(5):440-7. PMC: 3711863. DOI: 10.1038/nbt.2565. View

Kepecs A, Fishell G . Interneuron cell types are fit to function. Nature. 2014; 505(7483):318-26. PMC: 4349583. DOI: 10.1038/nature12983. View

Lam A, Deck G, Goldman A, Eskandar E, Noebels J, Cole A . Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat Med. 2017; 23(6):678-680. PMC: 5461182. DOI: 10.1038/nm.4330. View

Howard M, Rubenstein J, Baraban S . Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. Proc Natl Acad Sci U S A. 2013; 111(1):492-7. PMC: 3890856. DOI: 10.1073/pnas.1307784111. View

10.

Gurevicius K, Lipponen A, Tanila H . Increased cortical and thalamic excitability in freely moving APPswe/PS1dE9 mice modeling epileptic activity associated with Alzheimer's disease. Cereb Cortex. 2012; 23(5):1148-58. DOI: 10.1093/cercor/bhs105. View

11.

Bakker A, Krauss G, Albert M, Speck C, Jones L, Stark C . Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012; 74(3):467-74. PMC: 3351697. DOI: 10.1016/j.neuron.2012.03.023. View

12.

Palop J, Jones B, Kekonius L, Chin J, Yu G, Raber J . Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003; 100(16):9572-7. PMC: 170959. DOI: 10.1073/pnas.1133381100. View

13.

Cobos I, Long J, Thwin M, Rubenstein J . Cellular patterns of transcription factor expression in developing cortical interneurons. Cereb Cortex. 2006; 16 Suppl 1:i82-8. DOI: 10.1093/cercor/bhk003. View

14.

Zipancic I, Calcagnotto M, Piquer-Gil M, Mello L, Alvarez-Dolado M . Transplant of GABAergic precursors restores hippocampal inhibitory function in a mouse model of seizure susceptibility. Cell Transplant. 2010; 19(5):549-64. DOI: 10.3727/096368910X491383. View

15.

Hunt R, Girskis K, Rubenstein J, Alvarez-Buylla A, Baraban S . GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci. 2013; 16(6):692-7. PMC: 3665733. DOI: 10.1038/nn.3392. View

16.

Sederberg P, Schulze-Bonhage A, Madsen J, Bromfield E, McCarthy D, Brandt A . Hippocampal and neocortical gamma oscillations predict memory formation in humans. Cereb Cortex. 2006; 17(5):1190-6. DOI: 10.1093/cercor/bhl030. View

17.

Tong L, Djukic B, Arnold C, Gillespie A, Yoon S, Wang M . Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation. J Neurosci. 2014; 34(29):9506-15. PMC: 4099537. DOI: 10.1523/JNEUROSCI.0693-14.2014. View

18.

Alvarez-Dolado M, Calcagnotto M, Karkar K, Southwell D, Jones-Davis D, Estrada R . Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J Neurosci. 2006; 26(28):7380-9. PMC: 1550786. DOI: 10.1523/JNEUROSCI.1540-06.2006. View

19.

Mucke L, Masliah E, Yu G, Mallory M, Rockenstein E, Tatsuno G . High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000; 20(11):4050-8. PMC: 6772621. View

20.

Fazzari P, Paternain A, Valiente M, Pla R, Lujan R, Lloyd K . Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010; 464(7293):1376-80. DOI: 10.1038/nature08928. View