Inactivation of the GATA cofactor ZFPM1 results in abnormal development of dorsal raphe serotonergic neuron subtypes and increased anxiety-like behaviour.

Serotonergic neurons in the dorsal raphe (DR) nucleus are associated with several psychiatric disorders including depression and anxiety disorders, which often have a neurodevelopmental component. During embryonic development, GATA TFs GATA2 and GATA3 operate as serotonergic neuron fate selectors and regulate the differentiation of serotonergic neuron subtypes of DR. Here, we analysed the requirement of GATA cofactor ZFPM1 in the development of serotonergic neurons using Zfpm1 conditional mouse mutants. Our results demonstrated that, unlike the GATA factors, ZFPM1 is not essential for the early differentiation of serotonergic precursors in the embryonic rhombomere 1 (r1). In contrast, in perinatal and adult male and female Zfpm1 mutants, a lateral subpopulation of DR neurons (DRVL) was lost, whereas the number of serotonergic neurons in a medial subpopulation (DRD) had increased. Additionally, adult male and female Zfpm1 mutants had reduced serotonin concentration in rostral brain areas and displayed increased anxiety-like behaviour. Interestingly, female Zfpm1 mutant mice showed elevated contextual fear memory that was abolished with chronic fluoxetine treatment. Altogether, these results demonstrate the importance of ZFPM1 for the development of DR serotonergic neuron subtypes involved in mood regulation. It also suggests the neuronal fate selector function of GATAs is modulated by their cofactors to refine the differentiation of neuronal subtypes.SIGNIFICANCE STATEMENTPredisposition to anxiety disorders has both a neurodevelopmental and a genetic basis. One of the brainstem nuclei involved in the regulation of anxiety is the dorsal raphe, which contains different subtypes of serotonergic neurons. We show that inactivation of a transcriptional cofactor ZFPM1 in mice results in a developmental failure of laterally located dorsal raphe serotonergic neurons and changes in serotonergic innervation of rostral brain regions. This leads to elevated anxiety-like behaviour and contextual fear memory, alleviated by chronic fluoxetine treatment. Our work contributes to understanding the neurodevelopmental mechanisms that may be disturbed in the anxiety disorder.