MSK1 Mediates BDNF Signaling in Striatal Development, Affecting Psychiatric-Relevant Behaviors

Unraveling Molecular Pathways in Neurodevelopmental and Psychiatric Disorders

Brain-derived neurotrophic factor (BDNF) is a well-established regulator of neuronal health, and its dysregulation is implicated in conditions like major depressive disorder, bipolar disorder, and anxiety disorders [1, 2, 3]. Its levels are known to be modulated by clinical interventions including physical activity [4, 5], psychotherapy [6], and even probiotic supplementation [7]. However, a significant gap remains in understanding the specific downstream molecular mediators that execute BDNF's instructions within distinct neuronal populations, particularly during critical postnatal development [8]. Clarifying these intricate pathways is essential for moving beyond broad associations and developing more precise interventions for neurodevelopmental and psychiatric disorders.

MSK1: A Key Mediator in Postnatal Striatal Development

A recent study has identified mitogen- and stress-activated kinase 1 (MSK1) as a critical downstream mediator of BDNF signaling during the crucial period of postnatal striatal development. This kinase appears to play a specific and sustained role in this brain region. Researchers found that MSK1 expression is concentrated in GABAergic neurons, the primary inhibitory cells in the central nervous system, across both the cortex and the striatum. However, the expression pattern over time differed significantly between these regions. In cortical GABAergic interneurons, MSK1 expression declined between postnatal day 5 (P5) and day 30 (P30). In stark contrast, MSK1 expression in the striatum's GABAergic medium spiny neurons (MSNs) persisted into adulthood, suggesting a specialized and lasting function within the striatal circuits that govern motor function, reward, and cognition.

Striatal Structural Changes Linked to MSK1 Deficiency

To isolate the function of this kinase, the investigators created a mouse model with a targeted gene deletion (Msk1 IV KO). The findings in this model point to a highly localized role for MSK1 in maintaining striatal integrity. By postnatal day 60 (P60), mice lacking functional MSK1 exhibited a significant decrease in striatal volume and a reduction in the dendritic complexity of medium spiny neurons. This reduction in the elaborate branching of dendrites, which are essential for receiving and integrating signals, suggests a diminished capacity for synaptic communication within the striatum. Importantly, these structural deficits were specific to the striatum; the study found no corresponding alterations in cortical neurons. For clinicians, this specificity is noteworthy, as it links a single molecular deficiency to anatomical changes in a brain region deeply involved in motor control and executive function, deficits of which are hallmarks of numerous neurodevelopmental and psychiatric conditions.

Molecular Mechanism: MSK1, BDNF, and MeCP2 Phosphorylation

The study further delineated the precise molecular cascade through which MSK1 acts. The researchers demonstrated that MSK1 is directly responsible for BDNF-induced phosphorylation of MeCP2 at the serine 421 site within medium spiny neurons. MeCP2 (Methyl-CpG-binding protein 2) is a protein of high clinical interest, as its mutation or dysfunction causes Rett syndrome and is implicated in other disorders. This phosphorylation, a key process for activating or deactivating proteins, was shown to proceed through the MAPK/ERK signaling pathway and was notably independent of CaMKII. The investigation also revealed that MSK1 forms a nuclear complex with MeCP2, placing it directly at the site of gene regulation and amplifying its influence on transcription. This MSK1-MeCP2 signaling axis was found to be integral to both BDNF-dependent and independent processes that shape the physical structure of cultured striatal neurons. This discovery provides a mechanistic link between BDNF signaling and a protein, MeCP2, with known relevance to severe neurodevelopmental pathology.

Dysregulated Gene Expression and Behavioral Manifestations

The structural and molecular changes resulting from MSK1 deficiency culminated in altered gene expression and behavior. In the striatum of Msk1 IV KO mice, the researchers documented dysregulated expression of key GABAergic genes (Gad1, Gabrg3) and dopaminergic genes (Drd1, Drd2, Drd3). These genes are fundamental for regulating inhibitory neurotransmission and dopamine signaling, respectively. Critically, the authors note that this pattern of gene dysregulation mirrors profiles seen in models of MeCP2 deficiency, reinforcing the functional link between the two proteins. These molecular shifts were accompanied by a distinct behavioral phenotype. The Msk1 IV KO mice displayed hypersociability, impaired nest-building (a measure of complex, goal-directed behavior), and increased depressive-like behavior in the forced swimming test. For clinicians, this constellation of findings is significant, as it demonstrates how a single kinase deficiency can disrupt striatal circuits and produce behaviors relevant to psychiatric conditions, including altered social function, deficits in activities of daily living, and mood disturbances.

Clinical Implications: MSK1 as a Potential Therapeutic Target

This study constructs a coherent pathway from a specific molecular event to behaviors that model psychiatric symptoms. The findings establish that MSK1 deficiency leads to inhibitory circuit imbalances in the striatum, driven by downstream dysregulation of GABAergic and dopaminergic gene expression. These disruptions provide a plausible biological basis for the hypersociability, impaired self-care behaviors, and depressive-like states observed in the animal model. By identifying MSK1 as a key regulator of MeCP2 phosphorylation, the research positions MSK1 as a potential therapeutic target for a range of neurodevelopmental and psychiatric disorders, particularly those involving MeCP2 dysfunction or striatal circuit pathology. Interventions aimed at modulating MSK1 activity could, in theory, correct the downstream transcriptional and behavioral consequences, offering a more targeted strategy than is currently available for these complex conditions.

References

1. Zou Y, Zhang Y, Tu M, et al. Brain-derived neurotrophic factor levels across psychiatric disorders: A systemic review and network meta-analysis.. Progress in neuro-psychopharmacology & biological psychiatry. 2024. doi:10.1016/j.pnpbp.2024.110954

2. Liberona A, Jones N, Zúñiga K, et al. Brain-Derived Neurotrophic Factor (BDNF) as a Predictor of Treatment Response in Schizophrenia and Bipolar Disorder: A Systematic Review.. International journal of molecular sciences. 2024. doi:10.3390/ijms252011204

3. Luz ACDDSD, Dias GP, Bevilaqua MCDN, et al. Translational Findings on Brain-Derived Neurotrophic Factor and Anxiety: Contributions from Basic Research to Clinical Practice. Neuropsychobiology. 2013. doi:10.1159/000353269

4. Gan J, He J, Zhou K, et al. Effects of traditional Chinese exercises on brain-derived neurotrophic factor in middle-aged and older adults: A systematic review and meta-analysis of randomized controlled trials.. Journal of exercise science and fitness. 2025. doi:10.1016/j.jesf.2024.12.004

5. Schuch FB, Vancampfort D, Firth J, et al. Physical Activity and Incident Depression: A Meta-Analysis of Prospective Cohort Studies. American Journal of Psychiatry. 2018. doi:10.1176/appi.ajp.2018.17111194

6. Claudino F, Gonçalves L, Schuch F, Martins H, Rocha NSD. The Effects of Individual Psychotherapy in BDNF Levels of Patients With Mental Disorders: A Systematic Review. Frontiers in Psychiatry. 2020. doi:10.3389/fpsyt.2020.00445

7. Hashemi R, Raouf MMHM, Salih TS, et al. Impact of probiotic supplementation on serum levels of brain-derived neurotrophic factor: GRADE-based dose-response meta-analysis.. BMC nutrition. 2025. doi:10.1186/s40795-025-01152-9

8. Varela-Andrés N, Caño CH, Cebrián-León A, et al. MSK1 mediates BDNF-dependent MeCP2-S421 phosphorylation in postnatal striatal development and psychiatric-relevant behaviours.. Molecular psychiatry. 2026. doi:10.1038/s41380-026-03630-3