Epigenetic programming of stochastic olfactory receptor choice.

The mammalian sense of smell relies upon a vast array of receptor proteins to detect odorant compounds present in the environment. The proper deployment of these receptor proteins in olfactory sensory neurons is orchestrated by a suite of epigenetic processes that remodel the olfactory genes in differentiating neuronal progenitors. The goal of this review is to elucidate the central role of gene regulatory processes acting in neuronal progenitors of olfactory sensory neurons that lead to a singular expression of an odorant receptor in mature olfactory sensory neurons. We begin by describing the principal features of odorant receptor gene expression in mature olfactory sensory neurons. Next, we delineate our current understanding of how these features emerge from multiple gene regulatory mechanisms acting in neuronal progenitors. Finally, we close by discussing the key gaps in our understanding of how these regulatory mechanisms work and how they interact with each other over the course of differentiation.

Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn.

Sensory feedback is integral for contextually appropriate motor output, yet the neural circuits responsible remain elusive. Here, we pinpoint the medial deep dorsal horn of the mouse spinal cord as a convergence point for proprioceptive and cutaneous input. Within this region, we identify a population of tonically active glycinergic inhibitory neurons expressing parvalbumin. Using anatomy and electrophysiology, we demonstrate that deep dorsal horn parvalbumin-expressing interneuron (dPV) activity is shaped by convergent proprioceptive, cutaneous, and descending input. Selectively targeting spinal dPVs, we reveal their widespread ipsilateral inhibition onto pre-motor and motor networks and demonstrate their role in gating sensory-evoked muscle activity using electromyography (EMG) recordings. dPV ablation altered limb kinematics and step-cycle timing during treadmill locomotion and reduced the transitions between sub-movements during spontaneous behavior. These findings reveal a circuit basis by which sensory convergence onto dorsal horn inhibitory neurons modulates motor output to facilitate smooth movement and context-appropriate transitions.

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing.

Somatostatin interneurons are the earliest born population of cortical 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 in mouse somatosensory cortex 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. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons.

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.

Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism.

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.