Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice

Abstract

The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.

The effect of Cyanidin-3-o-glucoside on UVA-induced damage in human dermal fibroblasts

“…Decreased ERK phosphorylation induced by oxidative stress leads to toxic effects on brain development . Additionally, mouse neuronal apoptosis within 6 days after birth can be induced by the transient blockade of ERK activation . Inhibition of ERK activity down‐regulates expression of the anti‐apoptotic protein Bcl‐2, promotes caspase‐3 activation, and leads to programmed cell death through apoptosis .…”

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

“…In mouse models, there may be a critical developmental period when ERK1/2 dysregulation may result in autistic features. Phospho-blockade of ERK1/2 at postnatal day 6 (P6), but not at P14 leads to the development of autistic-like behaviors in adult mice (Yufune et al, 2015). A conditional ERK2 knockout mouse expresses a phenotype marked by aggressive behavior, reduced social behaviors, and learning deficits(Satoh et al, 2011), which are findings potentially consistent with an autism-like phenotype.…”

Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo

“…Subsequently it was shown that ERK activation is important for LTD and plays a critical role in mammalian learning and memory1516171819202122. Additional studies suggest that ERK phosphorylation is required for proper development of neuronal functions and its inhibition leads to the development of autistic phenotypes in mice23.…”