It has long been established that neuronal growth cone navigation depends on changes in microtubule (MT) and F-actin architecture downstream of guidance cues. However, the mechanisms by which MTs and F-actin are dually coordinated remain a fundamentally unresolved question. Here, we report that the well-characterized MT polymerase, XMAP215 (also known as CKAP5), plays an important role in mediating MT-F-actin interaction within the growth cone. We demonstrate that XMAP215 regulates MT-F-actin alignment through its N-terminal TOG 1-5 domains. Additionally, we show that XMAP215 directly binds to F-actin in vitro and co-localizes with F-actin in the growth cone periphery. We also find that XMAP215 is required for regulation of growth cone morphology and response to the guidance cue, Ephrin A5. Our findings provide the first strong evidence that XMAP215 coordinates MT and F-actin interaction in vivo. We suggest a model in which XMAP215 regulates MT extension along F-actin bundles into the growth cone periphery and that these interactions may be important to control cytoskeletal dynamics downstream of guidance cues. This article has an associated First Person interview with the first author of the paper.

There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of Δ 9 -tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation.

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Summary Attention deficit hyperactivity disorder is a chronic neurodevelopmental disorder, manifesting primarily as attention deficit, hyperactivity and impulsive behaviour. General anaesthetics can be neurotoxic, affecting neuronal differentiation and synaptogenesis, which can lead to abnormalities of cognition, learning and behaviour. We hypothesise that exposure of the immature brain to general anaesthetics predisposes to the development of attention deficit hyperactivity disorder. In this review, we summarise clinical and animal studies that relate attention deficit hyperactivity disorder to general anaesthesia, by actions on neural molecular mechanisms and neural networks. We also describe potential therapeutic approaches to modulate these effects.

Sevoflurane, in particular multiple exposures, has been reported to cause the abnormal neurological development including attention-deficit/hyperactivity disorder (ADHD). This study is to investigate ADHD-like impulsivity in adult mice after repeated sevoflurane exposures at the neonatal stage. Six-day-old pups were exposed to 60% oxygen in the presence or absence of 3% sevoflurane for 2 h and the treatment was administrated once daily for three consecutive days. To assess the impulsivity, the cliff avoidance reaction (CAR) was carried out at the 8th week. Our results showed that repeated sevoflurane treatment increased the number of jumps and shortened the jumping latency in the CAR test. The cortices were harvested for immunostaining to detect c-Fos and calmodulin-dependent protein kinase IIα (CaMKIIα) expression in the medial prefrontal cortex (mPFC). We found that mPFC neurons, especially excitatory neurons, were highly activated and related to impulsive behavior. The activation viruses (AAV-CaMKIIα-hM3Dq) were injected to evaluate the effects of specific activation of mPFC excitatory neurons on impulsive behavior in the presence of clozapine-N-oxide (CNO). Likewise, the inhibitory viruses (AAV-CaMKIIα-hM4Di) were injected in the sevoflurane group to explore whether the mPFC excitatory neuronal inhibition reduced the impulsivity. Our results revealed that chemogenetic activation of mPFC excitatory neurons induced impulsive behavior whereas inhibition of mPFC excitatory neurons partially rescued the deficit. These results indicate that repeated sevoflurane exposures at the critical time induce impulsive behavior accompanied with overactivation of mPFC excitatory neurons in adult stages. This work may further extend to understand the ADHD-like impulsive behavior of the anesthetic neurotoxicity.

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

Abl family kinases are essential regulators of cell shape and movement. Genetic studies revealed functional interactions between Abl kinases and microtubules (MTs), but the mechanism by which Abl family kinases regulate MTs remains unclear. Here, we report that Abl2 directly binds to MTs and regulates MT behaviors. Abl2 uses its C-terminal half to bind MTs, an interaction mediated in part through electrostatic binding to tubulin C-terminal tails. Using purified proteins, we found that Abl2 binds growing MTs and promotes MT polymerization and stability. In cells, knockout of Abl2 significantly impairs MT growth, and this defect can be rescued via reexpression of Abl2. Stable reexpression of an Abl2 fragment containing the MT-binding domain alone was sufficient to restore MT growth at the cell edge. These results show Abl2 uses its C-terminal half to bind MTs and directly regulate MT dynamics.

Purpose: This study evaluated the efficacy of retrobulbar ropivacaine plus dexmedetomidine compared with systemic fentanyl in pediatric vitreoretinal (VR) surgery. Methods: This prospective double-blind, randomized controlled study was performed in 60 children undergoing VR surgery, age from 2 to 7 years. After general anesthesia, the following procedure was administrated: (1) retrobulbar block with 0.5% ropivacaine plus dexmedetomidine 1 μg/kg (group RD, n = 20), (2) retrobulbar block with 0.5% ropivacaine (group RB, n = 20), and (3) control group with general anesthesia only (group F, n = 20). Hemodynamics, postoperative pain scores, anesthetics consumption (remifentanil, propofol, fentanyl), and emergence agitation were recorded. Results: Respiratory depression was observed in 7 of the 20 patients in group F after the laryngeal mask airway was removed in the operating room, compared with none in groups RD and RB. All patients in group F required intraoperative rescue fentanyl (average intraoperative fentanyl consumption, 26.6 ± 12.6 μg per patient). Some rescue fentanyl was required in group RB (three patients required one dose of rescue fentanyl). Patients in group RD required none. Groups RD and RB reported lower pain scores than group F at 4 h postoperatively (RD group: P < 0.001; RB group: P =0.002); pain scores in group RD were lower than that in group F at 6 h postoperatively ( P < 0.001). Conclusion: Retrobulbar dexmedetomidine as an adjuvant to ropivacaine is a safe and effective alternative to systemic fentanyl. This regimen provides better pain management, hemodynamic stability, and stress response suppression in pediatric VR surgery.