Summary We demonstrate that cortical interneurons derived from ventral eminences, including the caudal ganglionic eminence, undergo programmed cell death. Moreover, with the exception of VIP interneurons, this occurs in a manner that is activity-dependent. In addition, we demonstrate that, within interneurons, Calcineurin, a calcium-dependent protein phosphatase, plays a critical role in sequentially linking activity to maturation (E15–P5) and survival (P5–P20). Specifically, embryonic inactivation of Calcineurin results in a failure of interneurons to morphologically mature and prevents them from undergoing apoptosis. By contrast, early postnatal inactivation of Calcineurin increases apoptosis. We conclude that Calcineurin serves a dual role of promoting first the differentiation of interneurons and, subsequently, their survival.

Summary Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.

SUMMARYTo achieve smooth motor performance in a rich and changing sensory environment, motor output must be constantly updated in response to sensory feedback. Although proprioception and cutaneous information are known to modulate motor output, it is unclear whether they work together in the spinal cord to shape complex motor actions such as locomotion. Here we identify the medial deep dorsal horn (mDDH) as a “hot zone” of convergent proprioception and cutaneous input for locomotion. Due to increased responsiveness to sensory input, inhibitory interneurons in the mDDH area are preferentially recruited in locomotion. To study inhibitory interneurons in this area, we utilize an intersectional genetic strategy to isolate and ablate a population of parvalbumin-expressing glycinergic interneurons in the mDDH (dPVs). Using histological and electrophysiological methods we find that dPVs integrate proprioceptive and cutaneous inputs while targeting ventral horn motor networks, suggesting a role in multimodal sensory processing for locomotion. Consistent with this, dPVs ablation alters step cycle parameters and kinematics in a speed and phase dependent manner. Finally, we use EMG muscle recordings to directly show that dPVs are part of a cutaneous-motor pathway. Our results indicate that dPVs form a critical node in the spinal sensorimotor circuitry.HighlightsInhibitory interneurons in the medial deep dorsal horn (mDDH), a “hot zone” of convergence cutaneous and proprioceptive inputs, are preferentially recruited during locomotion.We identified an inhibitory population of Glycinergic deep dorsal horn parvalbumin-expressing interneurons (dPVs) which are active during locomotion, integrate multimodal sensory inputs, and target motor networks.Ablation of dPVs reveals a state and phase-dependent role in modulation of locomotion parameters and kinematics.Electromyogram recordings demonstrate that dPVs modulate the cutaneous-evoked response in hindlimb muscles, establishing them as the first genetically identified inhibitory neurons in a cutaneous-motor pathway.

Somatostatin interneurons are the earliest born population of inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity.Moreover, in somatostatin interneurons, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function. Hence, our work demonstrates that the Nova family of proteins are centrally involved in coupling developmental neuronal activity to cortical circuit formation.