MSK1 absence hinders BDNF-dependent striatal neurodevelopment and leads to schizophrenia symptoms

Abstract

It 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.