Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation

Abstract

The widespread environmental contaminant β-methylamino-L-alanine (BMAA) is a developmental neurotoxicant that can induce long-term learning and memory deficits. Studies have shown high transplacental transfer of 3H-BMAA and a significant uptake in fetal brain. Therefore, more information on how BMAA may influence growth and differentiation of neural stem cells is required for assessment of the risk to the developing brain. The aim of this study was to investigate direct and mitotically inherited effects of BMAA exposure using primary striatal neurons and embryonic neural stem cells. The neural stem cells were shown to be clearly more susceptible to BMAA exposure than primary neurons. Exposure to 250 µM BMAA reduced neural stem cell proliferation through apoptosis and G2/M arrest. At lower concentrations (50–100 µM), not affecting cell proliferation, BMAA reduced the differentiation of neural stem cells into astrocytes, oligodendrocytes, and neurons through glutamatergic mechanisms. Neurons that were derived from the BMAA-treated neuronal stem cells demonstrated morphological alterations including reduced neurite length, and decreased number of processes and branches per cell. Interestingly, the BMAA-induced changes were mitotically heritable to daughter cells. The results suggest that early-life exposure to BMAA impairs neuronal stem cell programming, which is vital for development of the nervous system and may result in long-term consequences predisposing for both neurodevelopmental disorders and neurodegenerative disease later in life. More attention should be given to the potential adverse effects of BMAA exposure on brain development.

Hippocampal neural stem cells are more susceptible to the neurotoxin BMAA than primary neurons: effects on apoptosis, cellular differentiation, neurite outgrowth, and DNA methylation

“…Pregnant rats were euthanized by decapitation 29 , 30 and primary neuronal cell cultures were prepared from fetal hippocampus at embryonic day 18 as previously described 31 . In brief, a single-cell suspension was obtained by dissociating embryonic hippocampal cells in DMEM/F12 medium and 100,000 cells/cm 2 were plated on polylysine-treated 96-well plates.…”

“…MTT assay was performed as previously described 31 . Cell viability was measured after 24 h of BMAA exposure in primary neuronal and neural stem cells, and 24 h after the passage into the daughter cells.…”

“…Neural stem cell cultures were prepared from fetal rat hippocampus at embryonic day 15 as previously described 31 . In brief, 40,000 cells/cm 2 were plated in 75 cm 2 flasks precoated with poly-L-ornithine and fibronectin and maintained in N2 medium enriched with 10 ng/ml bFGF to keep the cells in an undifferentiated state.…”

The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) targets the olfactory bulb region

“…BMAA is a mixed glutamate receptor agonist that can act via multiple mechanisms including induction of oxidative stress, inhibition of melatonin synthesis (important neuroprotective hormone), disruption of neuronal stem cell proliferation and differentiation (Lobner 2009;Pierozan et al 2018a;Pierozan and Karlsson 2019), as well as triggering neuronal cell death (Karlsson et al 2011;Lobner 2009). Studies also show that BMAA may be associated with, or incorporated into, proteins (Dunlop et al 2013;Karlsson et al 2009a;Karlsson et al 2015b) and induce protein misfolding, accumulation of protein aggregates, intracellular fibril formation, increased protein ubiquitination, α-synuclein deposition and apoptosis, supporting a role for BMAA in the development of neurodegeneration (Karlsson et al 2015a(Karlsson et al , 2012(Karlsson et al , 2014; Neonatal exposure to BMAA can induce significant behavioral changes in adult rats including long-term cognitive impairment (Karlsson et al 2009b(Karlsson et al , 2009c(Karlsson et al , 2011.…”

Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury

“…In recent years, neuronal reprogramming by the conversion of non-neuronal cells into functional neurons has represented a substantial improvement in the field of repairing injured or diseased brains [12,13]. Previous studies have shown that postnatal and adult endogenous NP/SCs (eNP/SCs) located in the mammalian subventricular zone (SVZ) and subgranular zone can become mature neurons under suitable conditions [14,15]. However, SVZ-derived NP/SCs home in on the injured cortex to become reactive astrocytes, which contribute to astrogenesis after brain injury [16,17].…”