Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

SummaryStress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we show that neuron-specific, inducible in vivo ablation of the mitochondrial fission protein Drp1 causes ER stress, resulting in activation of the integrated stress response to culminate in neuronal expression of the cytokine Fgf21. Neuron-derived Fgf21 induction occurs also in murine models of tauopathy and prion disease, highlighting the potential of this cytokine as an early biomarker for latent neurodegenerative conditions.

Research efforts during the last decade have deciphered the basic molecular mechanisms governing mitochondrial fusion and fission. We now know that in mammalian cells mitochondrial fission is mediated by the large GTPase dynamin-related protein 1 (Drp1) acting in concert with outer mitochondrial membrane (OMM) proteins such as Fis1, Mff, and Mief1. It is also generally accepted that organelle fusion depends on the action of three large GTPases: mitofusins (Mfn1, Mfn2) mediating membrane fusion on the OMM level, and Opa1 which is essential for inner mitochondrial membrane fusion. Significantly, mutations in Drp1, Mfn2, and Opa1 have causally been linked to neurodegenerative conditions. Despite this knowledge, crucial questions such as to how fission of the inner and outer mitochondrial membranes are coordinated and how these processes are integrated into basic physiological processes such as apoptosis and autophagy remain to be answered in detail. In this review, we will focus on what is currently known about the mechanism of mitochondrial fission and explore the pathophysiological consequences of dysregulated organelle fission with a special focus on neurodegenerative conditions, including Alzheimer's, Huntington's and Parkinson's disease, as well as ischemic brain damage.

OBJECTIVENeuroendoscopic surgery using an ultrasonic aspirator represents a valid tool with which to perform the safe resection of deep-seated ventricular lesions, but the handling of neuroendoscopic instruments is technically challenging, requiring extensive training to achieve a steep learning curve. Simulation-based methods are increasingly used to improve surgical skills, allowing neurosurgical trainees to practice in a risk-free, reproducible environment. The authors introduce a synthetic, patient-specific simulator that enables trainees to develop skills for endoscopic ventricular tumor removal, and they evaluate the model’s validity as a training instrument with regard to realism, mechanical proprieties, procedural content, and handling.METHODSThe authors developed a synthetic simulator based on a patient-specific CT data set. The anatomical features were segmented, and several realistic 1:1 skull models with all relevant ventricular structures were fabricated by a 3D printer. Vascular structures and the choroid plexus were included. A tumor model, composed of polyvinyl alcohol, mimicking a soft-consistency lesion, was secured in different spots of the frontal horn and within the third ventricle. Neurosurgical trainees participating in a neuroendoscopic workshop qualitatively assessed, by means of a feedback survey, the properties of the simulator as a training model that teaches neuroendoscopic ultrasonic ventricular tumor surgery; the trainees rated 10 items according to a 5-point Likert scale.RESULTSParticipants appreciated the model as a valid hands-on training tool for neuroendoscopic ultrasonic aspirator tumor removal, highly rating the procedural content. Furthermore, they mostly agreed on its comparably realistic anatomical and mechanical properties. By the model’s first application, the authors were able to recognize possible improvement measures, such as the development of different tumor model textures and the possibility, for the user, of creating a realistic surgical skull approach and neuroendoscopic trajectory.CONCLUSIONSA low-cost, patient-specific, reusable 3D-printed simulator for the training of neuroendoscopic ultrasonic aspirator tumor removal was successfully developed. The simulator is a useful tool for teaching neuroendoscopic techniques and provides support in the development of the required surgical skills.