You are here

J Neurosci DOI:10.1523/JNEUROSCI.0811-17.2017

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease.

Publication TypeJournal Article
Year of Publication2017
AuthorsKim, J, Hughes, EG, Shetty, AS, Arlotta, P, Goff, LA, Bergles, DE, Brown, SP
JournalJ Neurosci
Volume37
Issue37
Pages9037-9053
Date Published2017 Sep 13
ISSN1529-2401
KeywordsAdaptation, Physiological, Amyotrophic Lateral Sclerosis, Animals, Cortical Excitability, Disease Progression, Male, Mice, Mice, Transgenic, Motor Neurons, Neocortex, Nerve Net, Neuronal Plasticity, Neurons, Pyramidal Tracts
Abstract

Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS. It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase monotonically with disease progression. Moreover, although all neuronal cell types tested exhibited abnormal functional properties, analysis of their gene expression demonstrated cell type-specific responses to the ALS-causing mutation. These findings suggest that therapies for ALS may need to be tailored for different cell types and stages of disease.

DOI10.1523/JNEUROSCI.0811-17.2017
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28821643?dopt=Abstract

Alternate JournalJ. Neurosci.
PubMed ID28821643
PubMed Central IDPMC5597984
Grant ListP30 NS050274 / NS / NINDS NIH HHS / United States
R01 NS098819 / NS / NINDS NIH HHS / United States