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.

Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice.

Heterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied synaptic transmission in the prefrontal cortex of a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory and inhibitory synaptic transmission onto deep layer projection neurons, resulting in a reduced excitatory:inhibitory balance, which were found to vary dynamically across neurodevelopment and result from distinct effects of reduced Chd8 expression within individual neuronal subtypes.

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.

Protocol for Patch-Seq of Small Interneurons.

Obtaining electrophysiological recordings and gene expression information from the same neuron (Patch-seq) brings forward a unique opportunity to study the transcriptional correlates of functional properties and vice versa. Here, we provide a detailed Patch-seq protocol tailored to the specialized demands of studying small interneurons. Focusing on the technically demanding process of transitioning between patch recordings and cell extraction, our protocol describes and troubleshoots steps for successfully collecting small interneurons, allowing for multi-modal Patch-seq interrogation of this crucial cell type.

High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics.

Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast neural photoactivation over the whole range of the visible spectrum.

Identification of Persistent and Resurgent Sodium Currents in Spiral Ganglion Neurons Cultured from the Mouse Cochlea.

In spiral ganglion neurons (SGNs), the afferent single units of the auditory nerve, high spontaneous and evoked firing rates ensure preservation of the temporal code describing the key features of incoming sound. During postnatal development, the spatiotemporal distribution of ion channel subtypes contributes to the maturation of action potential generation in SGNs, and to their ability to generate spike patterns that follow rapidly changing inputs. Here we describe tetrodotoxin (TTX)-sensitive Na currents in SGNs cultured from mice, whose properties may support this fast spiking behavior.

Phosphoinositide Modulation of Heteromeric Kv1 Channels Adjusts Output of Spiral Ganglion Neurons from Hearing Mice.

Unlabelled: Spiral ganglion neurons (SGNs) relay acoustic code from cochlear hair cells to the brainstem, and their stimulation enables electrical hearing via cochlear implants. Rapid adaptation, a mechanism that preserves temporal precision, and a prominent feature of auditory neurons, is regulated via dendrotoxin-sensitive low-threshold voltage-activated (LVA) K(+) channels. Here, we investigated the molecular physiology of LVA currents in SGNs cultured from mice following the onset of hearing (postnatal days 12-21).

Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis.

A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment.

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.