Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis

Abstract

Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of C9orf72 impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and longterm depression at the Schaffer collateral/commissural synapses at the area CA1 were reduced in the hippocampus of C9orf72 knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of C9orf72 knockout mice was incorrectly enriched in the dendritic regions of CA1 with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in C9orf72 knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity.

Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

“…We speculate that in our paradigm, these terms can also represent adaptive neuronal plasticity given that synapse density and network activity in C9 ALI-COs remained unchanged compared to controls at 150 DIV, despite a modest increase in cell loss. This is supported by recent studies providing evidence for synaptic plasticity at early disease stages in animal ALS or ALS/FTD models before its failure 48 , 49 . Long-term ALI-CO cultures could now provide an opportunity to explore the timing and causative relationship between synapse and neuronal loss, which could not be mechanistically examined before in a human disease context.…”

Estrogen Enhances Dendrite Spine Function and Recovers Deficits in Neuroplasticity in the prpTDP-43A315T Mouse Model of Amyotrophic Lateral Sclerosis

“…ALS and FTD are related diseases genetically and pathologically. Models of FTD, including TDP-43 models have shown impairments in plasticity of the hippocampus through long-term potentiation (LTP) and long-term depression (LTD) studies [ 25 , 26 , 90 , 91 ]. LTP and LTD are the functional correlates of increases and decreases of ionotropic glutamate receptors.…”

“…Measuring the persistence, growth, pruning, and morphology of dendritic spines gives insight to the capacity of cortical networks for plasticity. Critically, early dysfunction of synaptic plasticity has been observed in many neurodegenerative diseases including ALS-FTD [24][25][26]. Targeting the components underlying neuroplasticity is increasingly seen as having the potential to treat circuit dysfunction in these diseases [27].…”

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

“…Therefore, several genetic models are subjected to experiment the common pathological outcomes in ALS and FTD. Disruption of hippocampal synaptic plasticity is reported in C9orf72 -deficient mice in terms of reduced LTP and LTD [ 228 ]. Furthermore, amplitude of the Glu currents were reduced without changing the paired pulse in the hippocampal slices from UBQLN2P497H TG mice [ 227 ].…”