Directed fusion of transmitter-laden vesicles enables rapid intercellular signaling in the central nervous system and occurs at synapses within gray matter. Here we show that action potentials also induce the release of glutamate from axons in the corpus callosum, a white matter region responsible for interhemispheric communication. Callosal axons release glutamate by vesicular fusion, which induces quantal AMPA receptor-mediated currents in NG2 + glial progenitors at anatomically distinct axo-glial synaptic junctions. Glutamate release from axons was facilitated by repetitive stimulation and could be inhibited through activation of metabotropic autoreceptors. Although NG2 + cells form associations with nodes of Ranvier in white matter, measurements of conduction velocity indicated that unmyelinated fibers are responsible for glutamatergic signaling with NG2 + glia. This activitydependent secretion of glutamate was prevalent in the developing and mature mouse corpus callosum, indicating that axons within white matter both conduct action potentials and engage in rapid neuronglia communication.The white matter of the CNS contains axons that permit functional interactions among specialized brain regions. The prevailing view is that these axons blindly transmit electrical activity through the white matter to be translated into the release of chemical messengers at synapses in gray matter; this restricted secretion of neurotransmitters at or near terminal active zones helps to maintain the specificity of intercellular communication in the nervous system 1 . Indeed, terminal boutons are rare in white matter, which contains primarily myelinated and unmyelinated axons and a variety of glial cells 2 . Nevertheless, glutamate is released in an activity-dependent manner from white matter 3 , glial cells within these fiber tracts express glutamate receptors 4,5 and glutamate transporters are present to remove glutamate 6 . Furthermore, glutamate-induced excitotoxic damage to oligodendrocytes and their progenitors is often observed after ischemia 7 , which leads to a loss of myelin and is a contributing factor in cerebral palsy. Despite this evidence of glutamatergic signaling in white matter, the mechanisms responsible for glutamate release within these projection pathways have not been determined.Correspondence should be addressed to D.E.B. (dbergles@jhmi.edu).. Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2007 December 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTo define the mechanisms of glutamate release within white matter, we recorded from glial precursor cells that express the proteoglycan NG2 (NG2 + cells) in the corpus callosum; these cells represent a potential target of axon-derived glutamate, as they express ionotropic glutamate receptors 4 , make contact...

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

These data suggest that 74-85% of colorectal cancers express a Lgr5/Ascl2 associated signature and support the hypothesis that they derive from Lgr5(+)/Ascl2(+) crypt stem cells, not Bmi1(+) stem cells. However, Olfm4 was not found to be a useful marker of Lgr5(+) cells in normal colon or tumours. In this large series, Lgr5 expression is not associated with increased tumour aggressiveness, as might be expected from a cancer stem cell marker.

Extraneural metastatic disease of glioma is rare and poses unique therapeutic challenges. Increasingly, the ability to sequence genetic alterations in tumors has allowed for the identification of common oncogenic signatures such as the activating BRAFV600E mutation and may be useful in therapeutic decision making. We report two patients with widespread aggressive gliomas whose tumors were found to express the BRAFV600E mutation and then responded robustly albeit transiently when exposed to vemurafenib. Although both patients succumbed to their disease, our results suggest that targeting BRAF might be appropriate for patients with aggressive gliomas that express this mutation.

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Transthyretin/TTR gene mutations usually cause systemic amyloidotic diseases. Few TTR variants preferentially affect the central nervous system, manifesting as oculoleptomeningeal amyloidosis. Patients with TTR meningovascular amyloidosis often show dementia, however the neuropathologic features of dementia in these cases have not been elucidated. We report the neuropathologic findings from a brain autopsy of a 72-year-old man with the rare Tyr69His (Y69H) TTR gene variant, dementia and ataxia. Severe amyloid deposits were observed in the leptomeninges and in a subpial and subependymal distribution. Mass spectrometry analysis demonstrated that the amyloid deposits were comprised of over 80 % of the variant TTR. TTR was undetectable by mass spectrometry in the neocortex subjacent to the subpial amyloid deposits. Subpial TTR amyloid deposits were associated with brisk superficial reactive gliosis and siderosis in the neocortex and cerebellar cortex. Subependymal TTR amyloid deposits were associated with subjacent myelin pallor in the hippocampal outflow tract structures including the alveus, fimbria and fornix. Phospho-tau immunostains demonstrated transentorhinal-stage neurofibrillary degeneration (Braak stage II) which, in the absence of neocortical amyloid-beta and neuritic plaques, was indicative of primary age-related tauopathy (PART). However, distinctive phospho-tau aggregates were observed subjacent to the subpial TTR amyloid deposits in all regions of the neocortex, including the primary motor and striate cortices, suggesting a potential link between TTR amyloid and neocortical tauopathy. Our report reveals novel insights into the potential neuropathologic substrates of dementia in variant TTR amyloidosis that need to be investigated in larger autopsy series.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0216-0) contains supplementary material, which is available to authorized users.

Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho-tau/MAPT (p-MAPT) neuropathology since its regional propagation correlates with the degree of cognitive impairment in AD. Recent diffusion tensor imaging studies in AD suggest that increased diffusion in the fornix secondary to p-MAPT-related axonal injury could serve as a predictive biomarker of the risk of disease progression. However, our knowledge of p-MAPT neuropathology in the fornix is limited. To address this gap in knowledge, we examined p-MAPT neuropathology in the fornix and basal forebrain nuclei via AT8 immunohistochemistry in 39 brain autopsies spanning the spectrum of AD neuropathologic changes. We found that the fornix and its precommissural efferent target nuclei (septum and nucleus accumbens) demonstrated neuronal and thread-like p-MAPT neuropathology only in National Institute on Aging/Alzheimer Association (NIA/AA) stages B2 and B3 of neurofibrillary degeneration, consistent with involvement after (and propagation from) the hippocampal formation. Interestingly, although tau astrogliopathy was frequently observed in the mammillary bodies in stage B2, neuronal tauopathy was not observed in the postcommissural targets (mammillary bodies and anterior thalamic nucleus) until stage B3. Tauopathy in the nucleus basalis of Meynert was strongly correlated with p-MAPT-positive axons in the fornix, suggesting that projections to the hippocampus also likely contribute to fornix tauopathy. Our cross-sectional autopsy findings indicate that the fornix is involved by p-MAPT neuropathology secondary to hippocampal involvement by AD neuropathology. Furthermore, our findings are compatible with the goal of in vivo detection of p-MAPT-related axonal pathology in the fornix in AD as a possible biomarker of p-MAPT progression from the hippocampal formation and underscore a need for additional clinical-radiologic-pathologic correlation studies.

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