Biology subjects

Fivaz, M.

Publications and source records attributed to Fivaz, M..

3 recordsLinked to original sources

bioRxiv2026

A mitochondrial tipping point couples early hyperexcitability to late-stage failure in patient-derived ALS motor neurons

Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease characterized by profound alterations in energy metabolism and progressive degeneration of MNs. Evidence from patients and model systems point to MN hyperexcitability as an early hallmark of ALS. How altered electrical activity intersects with energy metabolism, however, remains largely unexplored. To directly examine this relationship, we performed long-term longitudinal recordings of neuronal firing and mitochondrial function in patient-derived MNs harboring the pathogenic TDP-43 mutation A382T, together with their isogenic controls. A382T MNs displayed an early, transient phase of hyperexcitability peaking around 35 days in culture, which was also observed in MNs carrying a different TDP-43 disease variant (M337V). This hyperexcitable phase coincided with elevated mitochondrial function (hyperpolarized membrane potential and accelerated electron flow across respiratory complexes) and was ultra-sensitive to mild Fo/F1 ATPase inhibition, revealing near maximal mitochondrial output to meet increased energy demands. This phase was followed by a sharp decline in A382T MN firing frequency, mitochondrial depolarization, and the loss of approximately 50% of firing-competent neurons. Acute bidirectional manipulations of MN firing rates elicited homeostatic mitochondrial responses, further demonstrating tight coupling between neuronal activity and mitochondrial metabolism. Together, these findings uncover a pathological trajectory in which early hyperexcitability drives mitochondrial hypermetabolism, with progressive erosion of mitochondrial capacity, ultimately leading to late-stage MN failure.

neuroscience↗

bioRxiv2021

Autism-associated CHD8 keeps proliferation of human neural progenitors in check by lengthening the G1 phase of the cell cycle

CHD8 (Chromodomain Helicase DNA Binding Protein 8) is a chromatin remodeler that preferentially regulates expression of genes implicated in early development of the cerebral cortex. De novo mutations (DNMs) in CHD8 are strongly associated with a specific subtype of autism characterized by enlarged foreheads and distinct cranial features. The vast majority of these DNMs are heterozygous loss-of-function mutations with high penetrance for autism. How CHD8 haploinsufficiency alters the normal developmental trajectory of the human cortex is poorly understood and debated. Previous studies in the mammalian developing cortex have shown progressive lengthening of the G1 phase of the cell cycle as neural stem cells transition from proliferative to neurogenic divisions. G1 length has been proposed to operate as a molecular clock that controls timing of this crucial developmental switch. To determine the influence of CHD8 on cell cycle timing, we disrupted one allele of CHD8 in human embryonic stem cells (hESCs), differentiated these cells into neural precursor cells (NPCs), and imaged cell cycle progression of individual CHD8+/- NPCs -- in parallel with their isogenic CHD8+/+ counterparts -- during several rounds of cell division. We found a specific and marked decrease in G1 duration in CHD8+/- NPCs, resulting in an overall shortening of the cell cycle. Consistent with faster progression of CHD8+/- NPCs through G1 and the G1/S checkpoint, we observed increased expression of E cyclins and elevated phosphorylation of Erk in these mutant cells -- two central signalling pathways involved in S phase entry. Together, our findings show dysregulated proliferation of NPCs in a human stem cell model of CHD8 haploinsufficiency and predict enlargement of the neural progenitor pool in CHD8+/- developing brains, a phenotype that may explain macrocephaly in individuals with CHD8 DNMs. Furthermore, our work provides further evidence for a link between autism and cancer and identifies MAPK signaling as a potential therapeutic target for the treatment of this autism subtype.

neuroscience↗

bioRxiv2019

The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses

Lithium is a mood stabilizer broadly used to prevent and treat symptoms of mania and depression in people with bipolar disorder (BD). Little is known, however, about its mode of action. Here, we analyzed the impact of lithium on synaptic vesicle (SV) cycling at presynaptic terminals releasing glutamate, a neurotransmitter previously implicated in BD and other neuropsychiatric conditions. We used the pHluorin-based synaptic tracer vGpH and a fully automated image processing pipeline to quantify the effect of lithium on both SV exocytosis and endocytosis in hippocampal neurons. We found that lithium selectively reduces SV exocytic rates during electrical stimulation, and markedly slows down SV recycling post-stimulation. Analysis of single bouton responses revealed the existence of functionally distinct excitatory synapses with varying sensitivity to lithium [-] some terminals show responses similar to untreated cells, while others are markedly impaired in their ability to recycle SVs. While the cause of this heterogeneity is unclear, these data indicate that lithium interacts with the SV machinery and influences glutamate release in a large fraction of excitatory synapses. Together, our findings show that lithium down modulates SV cycling, an effect consistent with clinical reports indicating hyperactivation of glutamate neurotransmission in BD.

neuroscience↗