Transcription factors Satb1 and Satb2 regulate glutamate receptor gene expression and neuronal calcium signaling in mouse cortical neurons.

The transcription factors Satb1 and Satb2 are crucial for the development of the cortex and the maturation of neurons. Dysregulation in the expression of genes targeted by Satb1 and Satb2 has been linked to neurodegenerative processes, yet the precise molecular and cellular mechanisms by which these factors regulate neurotransmission are not well understood. This knowledge gap is significant because glutamate receptors—including NMDA, AMPA, and KA types—are central to excitatory signaling in the brain, and their malfunction is implicated in numerous neurological disorders. Understanding how Satb1 and Satb2 orchestrate the expression of these vital receptor subunits could reveal new therapeutic targets for conditions characterized by excitotoxicity or impaired neuronal communication.

This study investigated the role of Satb1 and Satb2 in regulating glutamate and GABA(A) receptor gene expression using a mouse model. The researchers utilized cortical neurons derived from several mouse lines: Satb1-deficient (Satb1fl/+ * NexCre/+), Satb1-null (Satb1fl/fl * NexCre/+), and mice with Satb2 deletions. They assessed gene expression changes and analyzed neuronal responses by measuring calcium signals (Ca2+-signals). The neurons were treated with selective agonists for different glutamate receptors—including an NMDA receptor agonist, 5-Fluorowillardiine (FW) for AMPA receptors, and domoic acid for kainate (KA) receptors—to probe the functional consequences of the genetic deletions.

Deletion of either Satb1 or Satb2 induced the expression of genes encoding NMDA receptor subunits, resulting in higher amplitude Ca2+-signals and a reduced EC50 for the NMDA receptor agonist. Concurrently, the expression of the Gria2 gene, which encodes an AMPA receptor subunit, was increased, paradoxically leading to decreased Ca2+-signals in response to the AMPA agonist FW. The study also found complex effects on KA receptor sensitivity.

Deletion of Satb1 increased the KA receptor's sensitivity to domoic acid in cortical neurons from Satb1-deficient mice, but decreased it in Satb1-null mice. Satb2 deletion consistently decreased Ca2+-signals and KA receptor sensitivity in both Satb1-null and Satb1-deficient mice. Furthermore, Satb1 deletion was shown to suppress neuron maturation and impair the switch of GABAergic responses from excitatory to inhibitory, an effect also observed with Satb2 deletion but only in the Satb1-null background.