SATB1 DELETION IN CORTICAL INTERNEURONS LEADS TO AN ABERRANT CORTICAL INHIBITORY NETWORK AND AUTISM-LIKE BEHAVIORS

GABAergic interneurons comprise 15-25% of all neurons in the cortex. They have multiple roles, from maintaining excitation/inhibition balance and synchronizing brain activity, to refining cortical processing in unique and multiple ways. Their functional diversity is enabled through their remarkable heterogeneity at the molecular, morphological and electrophysiological level. This diversity, although begins from early embryonic stages, is better manifested at postnatal stages, when interneurons acquire their mature properties via inducing additional genetic programs, as a response to emerging environmental cues, such as network activity.
We have previously shown that Satb1 is an activity-regulated transcription factor that is expressed at late embryonic stages, in the lineages of MGE-derived, parvalbumin (PV) and somatostatin (SST)-expressing interneurons, and it is implicated in their differentiation (Denaxa et al., 2012). Here we investigate the cell-autonomous mechanism of Satb1 function in cortical interneurons. We provide evidence that in the absence of Satb1 function, MGE-derived cortical interneurons show an aberrant transcriptional profile, with genes implicated in synapse organization, ion channel transmission, and neuropeptide regulation being down-regulated. These data are further supported, by defects in the morphology, as well as synapse number, of Satb1 mutant interneurons, both in vivo and in vitro. This disrupted inhibitory network, results in the manifestation of autism-like behaviors, in Satb1cKO mice.
We conclude that SATB1 orchestrates a late-onset developmental molecular program in cortical interneurons, that when disturbed contributes to the onset of autism.