Rapid presynaptic maturation in naturally regenerating axons of the adult mouse olfactory nerve.

Successful neuronal regeneration requires the reestablishment of synaptic connectivity. This process requires the reconstitution of presynaptic neurotransmitter release, which we investigate here in a model of entirely natural regeneration. After toxin-induced injury, olfactory sensory neurons in the adult mouse olfactory epithelium can regenerate fully, sending axons via the olfactory nerve to reestablish synaptic contact with postsynaptic partners in the olfactory bulb. Using electrophysiological recordings in acute slices, we find that, after initial recontact, functional connectivity in this system is rapidly established. Reconnecting presynaptic terminals have almost mature functional properties, including high release probability and strong capacity for presynaptic inhibition. Release probability then matures quickly, rendering reestablished terminals functionally indistinguishable from controls just 1 week after initial contact. These data show that successful synaptic regeneration in the adult mammalian brain is almost a "plug-and-play" process, with presynaptic terminals undergoing a rapid phase of functional maturation as they reintegrate into target networks.

Brief Sensory Deprivation Triggers Cell Type-Specific Structural and Functional Plasticity in Olfactory Bulb Neurons.

Can alterations in experience trigger different plastic modifications in neuronal structure and function, and if so, how do they integrate at the cellular level? To address this question, we interrogated circuitry in the mouse olfactory bulb responsible for the earliest steps in odor processing. We induced experience-dependent plasticity in mice of either sex by blocking one nostril for one day, a minimally invasive manipulation that leaves the sensory organ undamaged and is akin to the natural transient blockage suffered during common mild rhinal infections. We found that such brief sensory deprivation produced structural and functional plasticity in one highly specialized bulbar cell type: axon-bearing dopaminergic neurons in the glomerular layer. After 24 h naris occlusion, the axon initial segment (AIS) in bulbar dopaminergic neurons became significantly shorter, a structural modification that was also associated with a decrease in intrinsic excitability. These effects were specific to the AIS-positive dopaminergic subpopulation because no experience-dependent alterations in intrinsic excitability were observed in AIS-negative dopaminergic cells. Moreover, 24 h naris occlusion produced no structural changes at the AIS of bulbar excitatory neurons, mitral/tufted and external tufted cells, nor did it alter their intrinsic excitability. By targeting excitability in one specialized dopaminergic subpopulation, experience-dependent plasticity in early olfactory networks might act to fine-tune sensory processing in the face of continually fluctuating inputs.SIGNIFICANCE STATEMENT Sensory networks need to be plastic so they can adapt to changes in incoming stimuli. To see how cells in mouse olfactory circuits can change in response to sensory challenges, we blocked a nostril for just one day, a naturally relevant manipulation akin to the deprivation that occurs with a mild cold. We found that this brief deprivation induces forms of axonal and intrinsic functional plasticity in one specific olfactory bulb cell subtype: axon-bearing dopaminergic interneurons. In contrast, intrinsic properties of axon-lacking bulbar dopaminergic neurons and neighboring excitatory neurons remained unchanged. Within the same sensory circuits, specific cell types can therefore make distinct plastic changes in response to an ever-changing external landscape.

siRNA delivery: from lipids to cell-penetrating peptides and their mimics.

To deliver siRNA for therapeutic use, several hurdles must be addressed. Metabolic degradation must be blocked, and the RNAi cellular machinery is located in the cytoplasm, while double-stranded siRNA is large, highly charged and impermeable to cell membranes. To date, the solutions to the delivery issues have mostly involved different forms of lipid particle encapsulation. Cell-penetrating peptides and their mimics or analogues offer a different approach and this is an emerging field with the first in vivo examples now reported. Recent reports point to lipid receptors being involved in the cellular uptake of both types of transporter. This review examines the delivery of siRNA with a focus on cell-penetrating peptides and their small molecule and oligomeric mimics. The current status of siRNA delivery methods in clinical trials is examined. It now seems that the goal of delivering siRNA therapeutically is achievable but will they form part of a sustainable healthcare portfolio for the future.