Abstract
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 UBQLN2P497H 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 UBQLN2P497H 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 UBQLN2P497H 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by selective degeneration of motor neurons in the brain and spinal cord
No difference in paired-pulse ratio (PPR) was observed between the control and UBQLN2P497H animals at any of the time intervals investigated (9 and 12 cells, respectively, Figures 1C,D) suggesting that presynaptic mechanisms are unlikely to play an important role in the reduced glutamatergic current response
CA1 pyramidal neurons of 1-month old UBQLN2P497H mice display an overall decreased synaptic excitation that is the result of smaller macroscopic currents, while no change was detected in presynaptic release as determined using PPR
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by selective degeneration of motor neurons in the brain and spinal cord. It was previously reported that mutant UBQLN2P497H mice, which reproduce a mutation found in human ALS/FTD patients, are cognitively impaired (Gorrie et al, 2014). This impairment appears linked to proteasome impairment leading to the formation of aggregates in neuronal cell bodies and dendrites, and most markedly in dendritic spines. In Parkinson’s disease, on the other hand, direct and indirect pathway striatal spiny neurons show alterations of intrinsic excitability of opposite polarity, while synaptic connectivity is only affected in indirect pathway neurons (Fieblinger et al, 2014). A link between brain dysfunction and neuronal excitability is always present, the type (synaptic vs intrinsic) and polarity of the alterations are often unpredictable
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