Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.

Keywords: ALS; C9orf72; Excitotoxicity; FTD; RNA metabolism; Synaptic dysfunction.

Figure 1. Schematic depiction of morphological deficits contributing to synaptic dysfunction in ALS/FTD

Key features include alterations of dendritic arborization and changes in spine density and spine shape. These deficits have been commonly observed in cortical neurons, hippocampal neurons, and spinal motor neurons of ALS, FTD, and ALS/FTD models.

Figure 2. Schematic depiction of proposed mechanisms of altered excitability and excitotoxicty in ALS

Major contributing factors to altered excitability and excitotoxicty in spinal motor neurons and cortical neurons in ALS include reduced levels of astrocytic glutamate transporters, changes in AMPA receptors composition and function, and decreased inhibitory activity – all of which are hypothesized to cause excessive calcium load and subsequent neuronal cell death.

Figure 3. Schematic depiction of suggested mechanisms of altered excitability in FTD

In FTD and ALS/FTD models with primarily cognitive phenotypes, alterations in cortical and hippocampal excitability typically result in reduced excitability, as opposed to the hyperexcitability observed in primarily motor ALS. This may be due to aberrant expression of AMPARs and changes in their calcium permeability, as well as NMDAR dysfunction and toxic protein aggregation in neurites.