<p>Brain-derived neurotrophic factor (BDNF) is a master regulator of neuronal differentiation and inhibitory circuit maturation in the mammalian brain. Yet, its downstream mediators in distinct neuronal populations remain incompletely defined. Here, we identify mitogen- and stress-activated kinase 1 (MSK1) as a critical mediator of BDNF signalling during postnatal striatal development. MSK1 expression predominates in GABAergic neurons across the cortex and striatum, with region-specific dynamics: MSK1 expression in cortical GABAergic interneurons declines from postnatal day 5 (P5) to day 30 (P30), while expression in striatal GABAergic medium spiny neurons (MSNs) persists into adulthood. Using a novel <i>Msk1</i>^<i>IV</i> KO mouse model, generated by deleting exon IV of <i>Msk1</i>, we find that striatal volume and MSN dendritic complexity decrease by P60, without cortical neuron alterations, underscoring MSK1´s striatal-specific role. Mechanistically, MSK1 drives BDNF-induced MeCP2 phosphorylation at serine 421 in MSNs via MAPK/ERK, independently of CaMKII, forming a nuclear complex with MeCP2, thus amplifying MSK1´s role in transcriptional regulation. This MSK1-MeCP2 signalling is also involved in BDNF-dependent and independent morphological developmental processes of cultured striatal neurons. Accordingly, <i>Msk1</i>^<i>IV</i> KO striatum shows dysregulated GABAergic (<i>Gad1, Gabrg3</i>) and dopaminergic (<i>Drd1, Drd2, Drd3</i>) gene expression, mirroring profiles in MeCP2 deficient models. Behaviourally, <i>Msk1</i>^<i>IV</i> KO mice display hypersociability, impaired nest-building, and increased depressive-like behaviour in the forced swimming test, contributing to striatal circuit dysfunction. These findings link MSK1-mediated molecular disruptions to inhibitory circuit imbalances and behaviours reminiscent of psychiatric disorders, positioning MSK1 as a potential therapeutic target for neurodevelopmental and psychiatric disorders, including those associated with MeCP2 dysfunction.</p>