A functional unbalance of TRPM8 and Kv1 channels underlies orofacial cold allodynia induced by peripheral nerve damage.

Cold allodynia is a debilitating symptom of orofacial neuropathic pain resulting from trigeminal nerve damage. The molecular and neural bases of this sensory alteration are still poorly understood. Here, using chronic constriction injury (CCI) of the infraorbital nerve (IoN) (IoN-CCI) in mice, combined with behavioral analysis, Ca imaging and patch-clamp recordings of retrogradely labeled IoN neurons in culture, immunohistochemistry, and adeno-associated viral (AAV) vector-based delivery , we explored the mechanisms underlying the altered orofacial cold sensitivity resulting from axonal damage in this trigeminal branch.

Spike transmission failures in axons from cortical neurons .

The propagation of action potentials along axons is traditionally considered reliable due to the high safety factor for axonal spike transmission. However, numerical simulations suggest that high-frequency spikes could fail to invade distal axonal branches. To explore this experimentally , we used an axonal-targeted calcium indicator to image action potentials at axonal terminal branches in the superficial layers of mouse somatosensory cortical neurons.

Spike transmission failures in axons from mouse cortical pyramidal neurons in vivo.

The propagation of action potentials along axons is traditionally considered to be reliable, as a consequence of the high safety factor of action potential propagation. However, numerical simulations have suggested that, at high frequencies, spikes could fail to invade distal axonal branches. Given the complex morphologies of axonal trees, with extensive branching and long-distance projections, spike propagation failures could be functionally important.

Transport and localization on dendrite-inspired flat band linear photonic lattices.

The capacity of a physical system to transport and localize energy or information is usually linked to its spatial configuration. This is relevant for integration and transmission of signals as performed, for example, by the dendrites of neuronal cells. Inspired by recent works on the organization of spines on the surface of dendrites and how they promote localization or propagation of electrical impulses in neurons, here we propose a linear photonic lattice configuration to study how the geometric features of a dendrite-inspired lattice allows for the localization or propagation of light on a completely linear structure.

Voltage compartmentalization in dendritic spines in vivo.

Dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain. Spines are biochemical compartments but might also electrically modify synaptic potentials. Using two-photon microscopy and a genetically encoded voltage indicator, we measured membrane potentials in spines and dendrites from pyramidal neurons in the somatosensory cortex of mice during spontaneous activity and sensory stimulation.

Correction: Proliferation of Murine Midbrain Neural Stem Cells Depends upon an Endogenous Sonic Hedgehog (Shh) Source.

[This corrects the article DOI: 10.1371/journal.pone.

Non-conventional Axonal Organelles Control TRPM8 Ion Channel Trafficking and Peripheral Cold Sensing.

TRPM8 is the main ion channel responsible for cold transduction in the somatosensory system. Nerve terminal availability of TRPM8 determines cold sensitivity, but how axonal secretory organelles control channel delivery remains poorly understood. Here we examine the distribution of TRPM8 and trafficking organelles in cold-sensitive peripheral axons and disrupt trafficking by targeting the ARF-GEF GBF1 pharmacologically or the small GTPase RAB6 by optogenetics.

Golgi bypass for local delivery of axonal proteins, fact or fiction?

Although translation of cytosolic proteins is well described in axons, much less is known about the synthesis, processing and trafficking of transmembrane and secreted proteins. A canonical rough endoplasmic reticulum or a stacked Golgi apparatus has not been detected in axons, generating doubts about the functionality of a local route. However, axons contain mRNAs for membrane and secreted proteins, translation factors, ribosomal components, smooth endoplasmic reticulum and post-endoplasmic reticulum elements that may contribute to local biosynthesis and plasma membrane delivery.

The axonal endoplasmic reticulum: One organelle-many functions in development, maintenance, and plasticity.

The endoplasmic reticulum (ER) is highly conserved in eukaryotes and neurons. Indeed, the localization of the organelle in axons has been known for nearly half a century. However, the relevance of the axonal ER is only beginning to emerge.

IRE1 signaling exacerbates Alzheimer's disease pathogenesis.

Altered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress.

Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein the MVB/lysosomal pathway.

Brain regions affected by Alzheimer disease (AD) display well-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment β (C99), generated by cleavage of APP by β-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long-term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99.

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins.

The control of neuronal protein homeostasis or is tightly regulated both spatially and temporally, assuring accurate and integrated responses to external or intrinsic stimuli. Local or autonomous responses in dendritic and axonal compartments are crucial to sustain function during development, physiology and in response to damage or disease. Axons are responsible for generating and propagating electrical impulses in neurons, and the establishment and maintenance of their molecular composition are subject to extreme constraints exerted by length and size.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders.

ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders.

Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease.

Role of the unfolded protein response in organ physiology: lessons from mouse models.

The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and maturation of around one-third of the total proteome. Accumulation of misfolded proteins in the ER lumen engages a signal transduction pathway known as unfolded protein response (UPR) that feedback to recover ER homeostasis or to trigger apoptosis of irreversible damaged cells. The UPR is initiated by three main stress sensors including protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein 1α (IRE1α), which reprogram the genome through the control of downstream transcription factors.

Proliferation of murine midbrain neural stem cells depends upon an endogenous sonic hedgehog (Shh) source.

The Sonic Hedgehog (Shh) pathway is responsible for critical patterning events early in development and for regulating the delicate balance between proliferation and differentiation in the developing and adult vertebrate brain. Currently, our knowledge of the potential role of Shh in regulating neural stem cells (NSC) is largely derived from analyses of the mammalian forebrain, but for dorsal midbrain development it is mostly unknown. For a detailed understanding of the role of Shh pathway for midbrain development in vivo, we took advantage of mouse embryos with cell autonomously activated Hedgehog (Hh) signaling in a conditional Patched 1 (Ptc1) mutant mouse model.

The unfolded protein response in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR).