Abstract
Modulation of behavioural responses by neuronal signalling pathways remains incompletely understood. Signalling via mitogen-activated protein (MAP) kinase cascades regulates multiple neuronal functions. Here, we show that neuronal p38α, a MAP kinase of the p38 kinase family, has a critical and specific role in modulating anxiety-related behaviour in mice. Neuron-specific p38α-knockout mice show increased levels of anxiety in behaviour tests, yet no other behavioural, cognitive or motor deficits. Using CRISPR-mediated deletion of p38α in cells, we show that p38α inhibits c-Jun N-terminal kinase (JNK) activity, a function that is specific to p38α over other p38 kinases. Consistently, brains of neuron-specific p38α-knockout mice show increased JNK activity. Inhibiting JNK using a specific blood-brain barrier-permeable inhibitor reduces JNK activity in brains of p38α-knockout mice to physiological levels and reverts anxiety behaviour. Thus, our results suggest that neuronal p38α negatively regulates JNK activity that is required for specific modulation of anxiety-related behaviour.
Highlights
The mitogen-activated protein (MAP) kinase families c-Jun N-terminal kinases (JNKs) and p38 MAP kinases – together termed stress-activated protein kinases (SAPKs) – were mostly studied in the context of cellular stressors such as inflammatory cytokines and other danger signal molecules, UV radiation or osmotic stress[1]
Efficient neuron-restricted deletion in the resulting p38αΔNeu mice was confirmed by immunostaining of p38α and neuronal marker NeuN or astrocytic marker GFAP on hippocampal sections (Fig. S1A,B) and by immunoblot of cortical and hippocampal extracts (Fig. S1C). These results showed in addition that hippocampal levels of p38α protein are relatively higher as compared with cortical or cerebellar p38α levels (Fig. S1C). p38α expression was previously reported in central nervous system (CNS) cell types other than neurons[14,24]
Pan-neuronal p38α knockout mice reproduced at Mendelian ratio, were phenotypically normal and showed normal body weight gain as well as metabolism (Fig. S1D,E)
Summary
The MAP kinase families c-Jun N-terminal kinases (JNKs) and p38 MAP kinases – together termed stress-activated protein kinases (SAPKs) – were mostly studied in the context of cellular stressors such as inflammatory cytokines and other danger signal molecules, UV radiation or osmotic stress[1]. Our data suggest anxiety-related behaviour in mice is modulated through inhibition of JNK by neuronal p38α. To address functional consequences of neuronal deletion of p38α on behavioural and cognitive performance, we subjected 6-month old p38αΔNeu and p38αlox/lox control mice to a series of behaviour tests.
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