Highlights d Structures of the apo and ATPgS-bound AAA domain of katanin p60 are determined d The YRG motif of pore loop 1, unique to katanin, is crucial for katanin activity d Katanin remodels glutamylated microtubules and controls axon growth d Katanin and spastin recognize and remodel microtubules in distinct ways

Several studies have demonstrated the therapeutic potential of applying microtubule- (MT-) stabilizing agents (MSAs) that cross the blood-brain barrier to promote axon regeneration and prevent axonal dystrophy in rodent models of spinal cord injury and neurodegenerative diseases. Paradoxically, administration of MSAs, which have been widely prescribed to treat malignancies, is well known to cause debilitating peripheral neuropathy and axon degeneration. Despite the growing interest of applying MSAs to treat the injured or degenerating central nervous system (CNS), consequences of MSA exposure to neurons in the central and peripheral nervous system (PNS) have not been thoroughly investigated. Here, we have examined and compared the effects of a brain-penetrant MSA, epothilone B, on cortical and sensory neurons in culture and show that epothilone B exhibits both beneficial and detrimental effects, depending on not only the concentration of drug but also the type and age of a neuron, as seen in clinical settings. Therefore, to exploit MSAs to their full benefit and minimize unwanted side effects, it is important to understand the properties of neuronal MTs and strategies should be devised to deliver minimal effective concentration directly to the site where needed.

Recent evidence from genetics, animal model systems and biochemical studies suggests that defects in membrane trafficking play an important part in the pathophysiology of Parkinson’s disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) constitute the most frequent genetic cause of both familial and sporadic PD, and LRRK2 has been suggested as a druggable target for PD. Although the precise physiological function of LRRK2 remains largely unknown, mounting evidence suggests that LRRK2 controls membrane trafficking by interacting with key regulators of the endosomal-lysosomal pathway and synaptic recycling. In this review, we discuss the genetic, biochemical and functional links between LRRK2 and membrane trafficking. Understanding the mechanism by which LRRK2 influences such processes may contribute to the development of disease-modifying therapies for PD.

Fear conditioning has been used to study pathogenic mechanisms underlying anxiety disorders. Several studies have shown that humans with anxiety disorders exhibit strong fear responses during the acquisition of conditioned fear. However, there have been no studies investigating whether basal anxiety within the normal range is related to conditioned fear in rodents. We hypothesized that individual differences in conditioned fear are correlated to the basal anxiety level of each individual. To test this hypothesis, we measured the basal anxiety of mice by using the elevated-plus maze (EPM) and open field test (OFT) and correlated these data with contextual freezing during contextual fear conditioning (CFC). Strong correlation was found between the basal anxiety level measured in the OFT and contextual freezing in the CFC. Baseline freezing was also strongly correlated with the contextual freezing level during the retrieval phase of CFC. However, the basal anxiety level measured in the EPM was correlated neither with conditioned fear nor with baseline freezing in the CFC. These results suggest that both basal anxiety in the OFT and baseline freezing are related to contextually conditioned fear.

Neur1 and Neur2, mouse homologs of the Drosophila neur gene, consist of two neuralized homology repeat domains and a RING domain. Both Neur1 and Neur2 are expressed in the whole adult brain and encode E3 ubiquitin ligases, which play a crucial role in the Notch signaling pathways. A previous study reported that overexpression of Neur1 enhances hippocampus-dependent memory, whereas the role of Neur2 remains largely unknown. Here, we aimed to elucidate the respective roles of Neur1 and Neur2 in hippocampus-dependent memory using three lines of genetically modified mice: Neur1 knockout , Neur2 knockout , and Neur1 and Neur2 double knockout (D-KO). Our results showed that spatial memory was impaired when both Neur1 and Neur2 were deleted, but not in the individual knockout of either Neur1 or Neur2. In addition, basal synaptic properties estimated by input-output relationships and paired-pulse facilitation did not change, but a form of long-term potentiation that requires protein synthesis was specifically impaired in the D-KO mice. These results collectively suggest that Neur1 and Neur2 are crucially involved in hippocampusdependent spatial memory and synaptic plasticity.

Food deprivation can affect performance on difficult cognitive task, such as the delayed nonmatch-to-place T-maze task (DNMT). The importance of food deprivation on maintaining high motivation for DNMT task has been emphasized, but not many studies have investigated the optimal conditions for depriving rodents to maximize performance. Establishing appropriate conditions for food deprivation is necessary to maintain DNMT task motivation. We applied different conditions of food deprivation (1-h food restriction vs. 1.5-g food restriction; single caging vs. group caging) and measured body weight and the number of correct choices that 8-week-old C57BL/6J mice made during the DNMT task. The 1.5-g food restriction group maintained 76.0±0.6% of their initial body weight, but the final body weight of the 1-h food restriction condition group was reduced to 62.2±0.8% of their initial body weight. These results propose that 1.5-g food restriction condition is effective condition for maintaining both body weight and motivation to complete the DNMT task.

Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration‐associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real‐time reverse transcription polymerase chain reaction. Furthermore, the RNA‐seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham‐operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex‐dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.

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