scholarly journals Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

2020 ◽  
Author(s):  
T.M. Klein Gunnewiek ◽  
A. H. A. Verboven ◽  
M. Hogeweg ◽  
C. Schoenmaker ◽  
H. Renkema ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Synaptic Function ◽  
Network Activity ◽  
Patient Specific ◽  
List Type ◽  
Neuronal Network Activity ◽  
Expression Of Genes ◽  
Cultured Astrocytes ◽  
Specific Manner ◽  
Vesicle Cycle

SummaryMitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is often caused by an adenine to guanine mutation at m.3243 (m.3243A>G) of the MT-TL1 gene (tRNAleu(UUR)). To understand how this mutation affects the nervous system, we differentiated human induced-pluripotent stem cells (iPSCs) into excitatory neurons with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function from MELAS patients with the m.3243A>G mutation. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found that the m.3243A>G mutation affects expression of genes involved in mitochondrial respiration- and presynaptic function, as well as non-cell autonomous processes in co-cultured astrocytes. Finally, we show that the clinical II stage drug sonlicromanol (KH176) improved neuronal network activity in a patient-specific manner when treatment is initiated early in development. This was intricately linked with changes in the neural transcriptome. Overall, MEA-seq is a powerful approach to identify mechanisms underlying the m.3243A>G mutation and to study the effect of pharmacological interventions in iPSC-derived neurons.Highlights- High m.3243A>G heteroplasmy leads to lower neuronal network activity and synchronicity- High heteroplasmy affects expression of genes involved in mitochondrial ATP production and the synaptic function / the presynaptic vesicle cycle- High neuronal heteroplasmy non cell autonomously affects gene expression in healthy co-cultured astrocytes- Sonlicromanol partially rescues neuronal network activity and transcriptome changes induced by high heteroplasmyeTOC BlurbUsing human inducible pluripotent stem cell-derived neurons with high levels of m.3243A>G heteroplasmy, Klein Gunnewiek et al. show transcriptome changes underlying the functional neuronal network phenotype, and how sonlicromanol can partially improve both this neuronal network phenotype, and the transcriptome changes, in a patient-specific manner.

scholarly journals Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

2021 ◽  
Author(s):  
Shan Wang ◽  
Jon-Ruben van Rhijn ◽  
Ibrahim A Akkouh ◽  
Naoki Kogo ◽  
Nadine Maas ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Synaptic Function ◽  
Network Activity ◽  
Loss Of Function ◽  
Functional Changes ◽  
Neuronal Network Activity ◽  
Camp Pathway ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
Pka Pathway

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, have been shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. To study the effect of decreased SETD1A function in human cells, we generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was mainly characterized by an overly synchronized network. In individual neurons, this network phenotype was reflected by increased somatodendritic complexity and elevated synaptic connectivity. We found that this network phenotype was driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with schizophrenia, synaptic transmission and glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, using pharmacological experiments targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/- cultures. In conclusion, our results illuminate key molecular, cellular and network abnormalities caused by SETD1A haploinsufficiency and demonstrate a direct link between SETD1A and the cAMP-dependent pathway in human neurons.

Desynchronisation of neuronal network activity in traumatic brain injury

2008 ◽  
Vol 39 (01) ◽  
Author(s):  
F Otto ◽  
J Opatz ◽  
R Hartmann ◽  
D Willbold ◽  
E Donauer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Network ◽  
Network Activity ◽  
Neuronal Network Activity

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

Influence of albumin dialysis (MARS) on neuronal network activity in vitro

2001 ◽  
Vol 39 ◽  
pp. 40-40
Author(s):  
J Loock ◽  
J Stange ◽  
S Mitzner ◽  
R Schmidt ◽  
E W Keefer ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Network Activity ◽  
Albumin Dialysis ◽  
Neuronal Network Activity

scholarly journals Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mouhamed Alsaqati ◽  
Vivi M. Heine ◽  
Adrian J. Harwood
Keyword(s):  
Neuronal Network ◽  
Electrode Array ◽  
Network Connectivity ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Pharmacological Intervention ◽  
Spatial Connectivity ◽  
Neuronal Network Activity

Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. Methods Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory–excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Limitations Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. Conclusions Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

Sign in / Sign up

Export Citation Format

Share Document