An Etiological Foxp2 Mutation Impairs Neuronal Gain in Layer VI Cortico-Thalamic Cells through Increased GABA_B/GIRK Signaling

A rare mutation affecting the Forkhead-box protein P2 (FOXP2) transcription factor causes a severe monogenic speech and language disorder. Mice carrying an identical point mutation to that observed in affected patients (Foxp2(+/R552H) mice) display motor deficits and impaired synaptic plasticity in the striatum. However, the consequences of the mutation on neuronal function, in particular in the cerebral cortex, remain little studied. Foxp2 is expressed in a subset of Layer VI cortical neurons. Here, we used Ntsrl-EGFP mice to identify Foxp2+ neurons in the mouse auditory cortex ex vivo. We studied the functional impact of the R552H mutation on the morphologic and functional properties of Layer VI cortical neurons from Ntsrl-EGFP; Foxp2(+/R552H) male and female mice. The complexity of apical, but not basal dendrites was significantly lower in Foxp2(+/R552H) cortico-thalamic neurons than in control Foxp2(+/+) neurons. Excitatory synaptic inputs, but not inhibitory synaptic inputs, were decreased in Foxp2(+/R552H) mice. In response, homeostatic mechanisms would be expected to increase neuronal gain, i.e., the conversion of a synaptic input into a firing output. However, the intrinsic excitability of Foxp2+ cortical neurons was lower in Foxp2(+/R552H) neurons. A-type and delayed-rectifier (DR) potassium currents, two putative transcriptional targets of Foxp2, were not affected by the mutation. In contrast, GABA(B)/GIRK signaling, another presumed target of Foxp2, was increased in mutant neurons. Blocking GIRK channels strongly attenuated the difference in intrinsic excitability between wild-type (WT) and Foxp2(+/R552H) neurons. Our results reveal a novel role for Foxp2 in the control of neuronal input/output homeostasis.