ERK2 Contributes to the Control of Social Behaviors in Mice

Abstract

Signaling through extracellular signal-regulated kinase (ERK) is important in multiple signal transduction networks in the CNS. However, the specific role of ERK2 in in vivo brain functions is not fully understood. Here we show that ERK2 play a critical role in regulating social behaviors as well as cognitive and emotional behaviors in mice. To study the brain function of ERK2, we used a conditional, region-specific, genetic approach to target Erk2 using the Cre/loxP strategy with a nestin promoter-driven cre transgenic mouse line to induce recombination in the CNS. The resulting Erk2 conditional knock-out (CKO) mice, in which Erk2 was abrogated specifically in the CNS, were viable and fertile with a normal appearance. These mice, however, exhibited marked anomalies in multiple aspects of social behaviors related to facets of autism-spectrum disorders: elevated aggressive behaviors, deficits in maternal nurturing, poor nestbuilding, and lower levels of social familiarity and social interaction. Erk2 CKO mice also exhibited decreased anxiety-related behaviors and impaired long-term memory. Pharmacological inhibition of ERK1 phosphorylation in Erk2 CKO mice did not affect the impairments in social behaviors and learning disabilities, indicating that ERK2, but not ERK1 plays a critical role in these behaviors. Our findings suggest that ERK2 has complex and multiple roles in the CNS, with important implications for human psychiatric disorders characterized by deficits in social behaviors.

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

“…Nonetheless, although unrelated to the poor-performing subgroup's OLM deficit, this depletion of hippocampal synapses containing measurable levels of p-ERK1/2 likely influences other BTBR phenotypes. A suggestion of relevant behaviors comes from evidence that sociability impairments, as found in BTBR mice, arise in mice with nestin-driven conditional knockout of ERK2 (McFarlane et al, 2008;Satoh et al, 2011). These results support the notion that synapses containing p-ERK1/2, either within or outside hippocampus, are critical for proper sociability, and thus the decreased density of p-ERK1/2 þ synapses observed here might contribute to the BTBR's social impairments.…”

Coadministration of Hydrogen Gas as Part of the Carrier Gas Mixture Suppresses Neuronal Apoptosis and Subsequent Behavioral Deficits Caused by Neonatal Exposure to Sevoflurane in Mice

“…4,16 Primary antibodies used in this study were antiactive caspase-3 (rabbit polyclonal; Cell Signaling Technology, Beverly, MA) and anti-4-hydroxy-2-nonenal (mouse monoclonal; Japan Institute for the Control of Aging, Shizuoka, Japan) antibodies. For fluorescence staining, Alexa-Fluor 546-conjugated anti-mouse IgG antibody (Life Technologies, Eugene, OR) was used as a secondary antibody.…”

“…3,4,16 All mice used in behavioral studies were agematched male littermates. The olfactory test was conducted as described previously, 3 with some modifications.…”

MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

“…For example, conditional deletion of Mapk1 in the CNS caused a mild phenotype in neurogenesis (Satoh et al, 2011b) and MAPK3 deficiency enhanced the phenotype in these mice, suggesting that the total MAPK activity is essential for normal CNS development. Interestingly, MAPK1-deficient mice exhibited marked abnormalities in social behaviors related to facets of autismspectrum disorders in humans (Satoh et al, 2011a). Blocking MAPK3 activity in these mice with a pharmacological inhibitor did not cause additional psychological impairments, suggesting that MAPK1 has a unique role in the CNS in the control of social behavior.…”