The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

Abstract

Following the discovery of the vasorelaxant properties of nitric oxide (NO) by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS) led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow (CBF). Anatomically, axons, dendrites, or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting CBF as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e., neuronal, glial, and vascular cells) also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…It is released by many neuronal subtypes, including fast-spiking interneurons. 174 ROS react with nitric oxide, and may finally generate more harmful reactive nitrogen species. 173 Therefore, the maintenance of ROS at low levels is critical for normal cell function.…”

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

“…The mechanisms for such variation are unclear, but are likely to involve differences in both signalling pathways and vascular anatomy [73]. For example, the involvement of NO varies between brain areas, both in terms of the magnitude of its contribution and whether it acts to mediate or modulate neurovascular coupling (as discussed in [74]). There also appear to be regional differences in the involvement of metabotropic glutamate receptor (mGluR) subtypes, as the mGluR5 antagonist MPEP decreases stimulation-evoked BOLD responses more in rat subcortical regions than in the neocortex [75].…”

“…The mechanisms underlying neurovascular coupling in a given situation will vary depending on expression patterns of key enzymes and receptors across different brain areas, as well as the local and global circuit dynamics engaged by a given task. For example, different subtypes of inhibitory interneurons presumably alter neurovascular coupling not only by the release of different vasoactive molecules, but also by regulating the activity of the local network (Lecrux and Hamel [3] in this issue; [74]), affecting glutamate release and second messenger production in excitatory neurons and astrocytes. As discussed above, the activity of these circuits and the reactivity of blood vessels may also be affected by global brain state as expressed in different levels of monoaminergic and cholinergic tone.…”

Effects of iodinated contrast media in a novel model for cerebral vasospasm

“…Unfortunately, current in vitro models of vasospasm that use whole blood to simulate SAH 8,9 are technically unsuitable for investigation of the autoregulation of cerebral vessels, mostly because presence of blood prevents visualization of a pressurized vessel and diameter measurements. We developed a novel, highly reproducible and technically uncomplicated model of vasospasm in vitro using a perfusion myograph and videomicroscopy to investigate the myogenic response of cerebral vessels -one of the main mechanisms of cerebral blood flow autoregulation 10,11 .…”