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Summary: Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons. : Genetic variants in the TMEM106B gene, coding for a lysosomal transmembrane protein, are linked to various neurodegenerative diseases. The function of TMEM106B remains enigmatic. Lüningschrör et al. analyze Tmem106b-knockout mice and find drastically enlarged LAMP1-positive vacuoles in proximal axons of selected motoneuron nuclei. Vacuolization is caused by impaired axonal transport. Keywords: TMEM106B, frontotemporal lobar degeneration, lysosome, retrograde, axon, axon initial segment, motoneurons, FTLD

Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditionalArc/Arg3.1knock-out (KO) mice to investigate the causal relationship betweenArc/Arg3.1deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Usingin vivolocal field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in whichArc/Arg3.1was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in whichArc/Arg3.1was deleted during late postnatal development. Our data show that constitutiveArc/Arg3.1KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal ofArc/Arg3.1 per sedoes not cause schizophrenia-like behavior. Prenatal or perinatal deletion ofArc/Arg3.1alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation ofArc/Arg3.1rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.SIGNIFICANCE STATEMENTThe activity-regulated and memory-linked geneArc/Arg3.1has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss ofArc/Arg3.1can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion ofArc/Arg3.1before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion ofArc/Arg3.1does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation ofArc/Arg3.1might critically imbalance brain networks and lead to emergence of schizophrenia.

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3, a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced β-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus.