Kalaitzidou, M; (2014) The Role of SATB1 in Medial Ganglionic Eminence-derived Cortical Interneuron Differentiation. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Brain function depends on the activity of cortical γ-aminobutyric acid- producing (GABAergic) interneurons, which participate in the formation of inhibitory circuits and control the activity of excitatory glutamatergic pyramidal neurons. Cortical GABAergic interneurons are extremely diverse in morphology, electrophysiology and molecular marker expression. A plethora of transcription factors that control aspects of this diversity has now been identified. Among them, the LIM-homeodomain transcription factor LHX6 is required for the differentiation of parvalbumin+ (PV+) and somatostatin+ (SST+) cortical interneurons. However, little is known about the molecular cascades operating downstream of LHX6 to control the maturation of these two major interneuron subtypes. With a focus on identifying region- and stage-specific factors regulating interneuron maturation, a genome-wide gene expression analysis was conducted in our laboratory and identified the gene encoding the chromatin organiser protein SATB1 as an LHX6 target in the E15.5 mouse cortex. In this thesis, we investigate the in vivo role of SATB1 in cortical interneuron terminal differentiation. Using a constitutive Satb1-null mouse established in our laboratory we demonstrate that Satb1 regulates multiple aspects of SST+ interneuron maturation. In contrast, by generating mice with a specific deletion of Satb1 in PV+ interneurons (PV-Cre;Satb1-flox) we show that Satb1 is not required for the maturation of this group of inhibitory neurons. Moreover, interneuron-specific deletion of Satb1 with the Nkx2.1-Cre line reveals a disruption of the excitation/inhibition balance in the brain and a significant loss of both SST+ and PV+ interneurons. Finally, we show that SATB1 and the general neuronal maturation marker KCC2 are coexpressed in mature cortical interneurons. By performing overexpression experiments in brain slices we observed regulation of Kcc2 expression by SATB1, but failed to detect any reciprocal regulation of Satb1 by KCC2. Overall, our findings provide a basis for understanding the terminal differentiation of interneurons in the mammalian cortex.

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