Early Impairment of Synaptic and Intrinsic Excitability in Mice Expressing ALS/Dementia-Linked Mutant UBQLN2

• Published in: Frontiers in cellular neuroscience Vol. 10; p. 216
• Main Authors: Radzicki, Daniel, Liu, Erdong, Deng, Han-Xiang, Siddique, Teepu, Martina, Marco
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 20.09.2016; Frontiers Media S.A
• Subjects: Action potential; Action Potentials; Afterhyperpolarization; AHP potassium current; Amyotrophic Lateral Sclerosis; Animal cognition; Brain; Cognitive ability; Dementia; Dementia disorders; Depolarization; Excitability; firing patterns; Firing rate; Frontotemporal dementia; Gene expression; Glucose; Glutamatergic transmission; Hippocampus; Laboratory animals; Motor neurons; Mutation; Neuroscience; Pyramidal cells; Sensory neurons; Synaptic Transmission; United States > US; Chicago Illinois; ALS/dementia; pyramidal cell; CA1; glutamate
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2016.00216

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are believed to represent the different outcomes of a common pathogenic mechanism. However, while researchers have intensely studied the involvement of motor neurons in the ALS/FTD syndrome, very little is known about the function of hippocampal neurons, although this area is critical for memory and other cognitive functions. We investigated the electrophysiological properties of CA1 pyramidal cells in slices from 1 month-old UBQLN2 mice, a recently generated model of ALS/FTD that shows heavy depositions of ubiquilin2-positive aggregates in this brain region. We found that, compared to wild-type mice, cells from UBQLN2 mice were hypo-excitable. The amplitude of the glutamatergic currents elicited by afferent fiber stimulation was reduced by ~50%, but no change was detected in paired-pulse plasticity. The maximum firing frequency in response to depolarizing current injection was reduced by ~30%; the fast afterhyperpolarization in response to a range of depolarizations was reduced by almost 10 mV; the maximum slow afterhyperpolarization (sAHP) was also significantly decreased, likely in consequence of the decreased number of spikes. Finally, the action potential (AP) upstroke was blunted and the threshold depolarized compared to controls. Thus, synaptic and intrinsic excitability are both impaired in CA1 pyramidal cells of UBQLN2 mice, likely constituting a cellular mechanism for the cognitive impairments. Because these alterations are detectable before the establishment of overt pathology, we hypothesize that they may affect the further course of the disease.