LAUSR

The findings published by Monnier et al. (2016) in this journal showing substantial cerebrovascular BDNF synthesis are very interesting and could change our way we perceive BDNF production in the brain under normal and disease states. BDNF is one of the classic neurotrophins first discovered in the 1950s and acts on TrkB and pan75 neurotrophin receptor (p75) receptors. TrkB signalling leads to increased proliferation and survival, whereas p75 signalling is less clear but has mostly been associated with cell damage and apoptosis (Ibanez & Simi 2012). BDNF has been shown to have widespread function within the brain with significant effects on neurogenesis, synaptogenesis, synaptic transmission and cognitive function. Overall, it has great therapeutic potential for many neurological disorders. In the elegant study by Monnier et al. (2016), they show that the vasculature, in contrast to most previous views, is a main source of BDNF in the brain. The strongest support for this comes from the removal of the brain endothelium in rats, by perfusion of a CHAPS solution through the brain vasculature, which resulted in around 50% lower levels of BDNF in the cortex and hippocampus compared to unperfused brains. This is a dramatic decrease considering the endothelium is believed to only constitute a few per cent of all cells in the brain and indicate a very high level of BDNF production in these cells. Production of BDNF by the brain vasculature is not a new finding; however, the great contribution of the cerebrovasculature to overall BDNF production in the brain has not been previously shown so clearly. This finding highlights the potential role for the vasculature as a player in brain function and health. In addition, by isolating the vasculature, they show that BDNF is constitutively made by the vasculature under normal conditions and can be augmented by exercise. The production of BDNF appears preserved throughout the cerebrovascular tree with isolated brain vessels fractionated by size, supposedly corresponding from larger vessels to small capillaries, showing similar levels of BDNF synthesis. Today, we view the vasculature as being tightly interconnected to other cells within each organ, with the brain vasculature maybe being the most specialized in the body. It harbours the blood–brain barrier (BBB), allowing for exact control of molecules that passes in and out of the brain. The BBB plays a crucial role in brain nutrition; therefore, important nutrients in the blood are allowed or facilitated to cross the endothelium provided for by various transporters on the endothelial cells. However, the brain vasculature lacks transporters for neurotrophins. The control and maintenance of the BBB does not just rely on the endothelium itself but also the pericytes embedded in the basement membrane surrounding the endothelial cells, with brain vasculature having the highest pericyte coverage in the body. Pericytes are central in providing trophic support for the endothelial cells and also have a crucial role in maintaining BBB integrity, thereby controlling transcytosis across these cells (Daneman & Prat 2015). Astrocytes that surround the whole endothelium also appear to control the brain endothelial function and are important in cerebrovascular coupling. This conceptualizes the cerebrovascular unit, which encompasses the endothelium with supporting cells such as pericytes and astrocytes, as a link from the endothelium to the neurones and vice versa. One such control that has been studied in more detail is the neural control over microvascular blood flow. The control of hyperaemia or increased blood flow appears dependent not only on direct control from neurones, but also astrocytes. Cerebrovascular coupling safeguards that glia and neurones receive an adequate supply of blood involving neurotransmitters such as glutamate, which probably functions both through neurones (and subsequent NO production) and astrocytes to mediate blood-flow coupling. The study by Monnier et al. (2016) provides further support of the vasculature as a neuromodulator and the strong link that exists between the endothelium and neurones. Previous studies on the role of cerebrovascular BDNF have been mainly restricted to its function on neurones within the subventricular zone (SVZ). BDNF provides trophic support for newborn neurones and has been shown to guide neuronal precursor cell migration from the subventricular zone to the olfactory bulb along the rostral migratory (Snapyan et al. 2009). Interestingly, a recent study has shown that