Deep subcortical lesions (DSCL) of the brain, are present in ~60% of the ageing population, and are linked to cognitive decline and depression. DSCL are associated with demyelination, blood brain barrier (BBB) dysfunction, and microgliosis. Microglia are the main immune cell of the brain. Under physiological conditions microglia have a ramified morphology, and react to pathology with a change to a more rounded morphology as well as showing protein expression alterations. This study builds on previous characterisations of DSCL and radiologically ‘normal-appearing’ white matter (NAWM) by performing a detailed characterisation of a range of microglial markers in addition to markers of vascular integrity. The Cognitive Function and Ageing Study (CFAS) provided control white matter (WM), NAWM and DSCL human post mortem tissue for immunohistochemistry using microglial markers (Iba-1, CD68 and MHCII), a vascular basement membrane marker (collagen IV) and markers of BBB integrity (fibrinogen and aquaporin 4). The immunoreactive profile of CD68 increased in a stepwise manner from control WM to NAWM to DSCL. This correlated with a shift from small, ramified cells, to larger, more rounded microglia. While there was greater Iba-1 immunoreactivity in NAWM compared to controls, in DSCL, Iba-1 levels were reduced to control levels. A prominent feature of these DSCL was a population of Iba-1-/CD68+ microglia. There were increases in collagen IV, but no change in BBB integrity. Overall the study shows significant differences in the immunoreactive profile of microglial markers. Whether this is a cause or effect of lesion development remains to be elucidated. Identifying microglia subpopulations based on their morphology and molecular markers may ultimately help decipher their function and role in neurodegeneration. Furthermore, this study demonstrates that Iba-1 is not a pan-microglial marker, and that a combination of several microglial markers is required to fully characterise the microglial phenotype.

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Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein. How C9orf72 haploinsufficiency contributes to disease has not been resolved. Here we identify the synapsin family of synaptic vesicle proteins, the most abundant group of synaptic phosphoproteins, as novel interactors of C9orf72 at synapses and show that C9orf72 plays a cell-autonomous role in the regulation of excitatory synapses. We mapped the interaction of C9orf72 and synapsin to the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin, and show interaction of the endogenous proteins in synapses. Functionally, C9orf72 deficiency reduced the number of excitatory synapses and decreased synapsin levels at remaining synapses in vitro in hippocampal neuron cultures and in vivo in the hippocampal mossy fibre system of C9orf72 knockout mice. Consistent with synaptic dysfunction, electrophysiological recordings identified impaired excitatory neurotransmission and network function in hippocampal neuron cultures with reduced C9orf72 expression, which correlated with a severe depletion of synaptic vesicles from excitatory synapses in the hippocampus of C9orf72 knockout mice. Finally, neuropathological analysis of post-mortem sections of C9ALS/FTD patient hippocampus with C9orf72 haploinsufficiency revealed a marked reduction in synapsin, indicating that disruption of the interaction between C9orf72 and synapsin may contribute to ALS/FTD pathobiology. Thus, our data show that C9orf72 plays a cell-autonomous role in the regulation of neurotransmission at excitatory synapses by interaction with synapsin and modulation of synaptic vesicle pools, and identify a novel role for C9orf72 haploinsufficiency in synaptic dysfunction in C9ALS/FTD.

Idiopathic hypertrophic spinal pachymeningitis (IHSP), a rare diffuse inflammatory thickening of the dura mater, and Guillain-Barré syndrome (GBS) are known entities but they have never been reported as concomitant diagnoses. To their knowledge, the authors present the first reported case in the international literature with supportive evidence for both IHSP (based on MRI, intraoperative, and histological findings) and GBS (based on history, clinical examination, and electrophysiological findings). They review the literature on IHSP and the diagnostic criteria for GBS, with the view of identifying a possible causative connection.