MSK1 expression in the GABAergic network and its relationship with striatal growth, BDNF-mediated MeCP2 phosphorylation and schizophrenia

Abstract

AbstractIt is becoming evident that impairments of the neuronal circuitry during development are the basis for some human disorders including autism and schizophrenia. To understand how synaptic wiring is formed and maintained is not only a major scientific challenge, but also has an important biomedical implication. The striatal GABAergic projection neurons, also called Medium Spiny Neurons (MSNs), represent more than 95% of the neuronal population in the striatum. This inhibitory brain hub is associated to voluntary body movements, reward-associated learning, and social behaviour control. The functional loss of the striatum has been associated with several neurological disorders including Huntington disease, Rett syndrome, and schizophrenia. The aetiology of these pathologies implies not only a decrease in the glutamatergic and dopaminergic inputs that reaches into the striatum, but also alterations of the GABAergic brain circuits occurring during development. Using a new MSK1 knockout murine model, we describe that mitogen- and stress-activated protein kinase-1 (MSK1) controls MSNs arborization during mouse brain development, phosphorylation of serine 421 in methyl-CpG binding protein-2 (MeCP2) and regulation of genes involved in gamma-aminobutyric acid (GABA) and dopamine functions, factors that finally cause behaviours reminiscent of schizophrenia in patients.Significance statementBrain development requires, at a cellular level, the coordinate action of extrinsic and intrinsic regulating factors to control the correct assembly of neuronal networks. Although much attention has been focussed on the action of extrinsic factors such as BDNF, it is still unclear how this neurotrophin is able to modulate responses in different cells. Here, through the analysis of a newMsk1 KOmouse model we identify a key role for MSK1, a kinase of the BDNF/MAPK pathway. We found that its expression is regulated during mouse brain development in GABAergic neurons. Through this approach, we have shown that MSK1 is an essential intrinsic factor of GABAergic neurons, participating during development in the control of striatal Medium Spiny Neurons arborization, in the activity of MeCP2, and in the expression of genes involved in the GABA and dopamine regulation in the striatum. Our results also demonstrate that the actions of MSK1 are essential for proper maturation of the striatal circuits and its absence can be related with schizophrenia-like symptoms in adult mice.