br A myriad of receptors in WM
A myriad of receptors in WM To complicate the picture, WM glia express numerous non-glutamatergic neurotransmitter receptors, a fact that is often underappreciated when considering pathophysiology. When examined in isolated optic nerve, a central WM tract completely devoid of neuronal synapses, receptor-mediated responses can be observed for ATP, GABA, nicotinic agonists, catecholamines, serotonin and glycine [19,37,54,90,94,98,119], see Ref. . While there is evidence that WM ATP receptors help to coordinate the complex morphological arrangement between glia and BX-912 australia , and GABA-A receptors may regulate glial cell number and myelination , other than GluRs there is little information on the physiological role of WM glial receptors. Despite this, there is growing evidence that WM glial receptors other than GluRs are important in pathological conditions such as multiple sclerosis, spinal cord injury, stroke, and cerebral palsy [2,19,57,68,92,, , ]; while we long ago demonstrated that activation of WM GABA-B or adenosine receptors can provide acute protection from ischemic injury [35,36]. In this regard, WM injury may parallel GM injury where it is thought that the loss of balance between excitatory and inhibitory neurotransmission is a necessary condition for functional loss (e.g. ). To illustrate the variety of glial receptor expression, we have previously examined neurotransmitter subunit mRNA was examined in adult isolated rat optic nerve (Fig. 1, adapted from ). mRNA expression examined in this preparation is almost exclusively of glial origin, which are made up of ∼35% astrocytes/65% oligodendrocytes in this tissue . This analysis reveals receptor expression levels in WM glial that are comparable to those found in GM for several receptor sub-units, e.g. the β3 subunit of the nAch receptor and the β1 subunit of the GABA-A receptor. Many of the receptor subunits shown to be expressed in WM in Fig. 1 are present at comparable levels relative to those in GM than shown for GluR subunits , indicating their potential relevance in ischemia. We have recently shown the potential for interaction between receptor types during modelled ischemia .
Mechanisms of glutamate homeostasis operating in WM Glutamate uptake from the extracellular space is conducted by specific glutamate transporters (GluT), and is essential for the shaping of excitatory postsynaptic currents and for the prevention of excitotoxic death due to overstimulation of GluRs . Of these, glutamate transporter 1 (GLT-1; also known as EAAT2) exhibits the highest level of adult expression, overwhelmingly in astrocytes, and it is responsible for most glutamate transport . The main transporter expressed by mature oligodendrocytes is glutamate aspartate transporter (GLAST; also known as EAAT1), whereas excitatory amino acid carrier 1 (EAAC1; or EAAT3), is present in a subpopulation of adult oligodendrocyte progenitor cells . It appears that all WM macroglial cells differentially express the three major GluTs. These transporters maintain basal levels of extracellular glutamate in the range of 1–2 μM and prevent over-activation of glutamate receptors under physiological conditions. In turn, glutamate transporters can contribute to glutamate release in WM by reversing Na+-dependent glutamate uptake in injured axons that suffer internal Na+ overload that reverses GluTs [24,25,102]; but see . In addition, glutamate homeostasis is also regulated by system xc−, a membrane-bound, Cl−-dependent, Na+-independent antiporter that mediates the cellular uptake of cystine in a 1:1 exchange for glutamate . System xc− is vital for antioxidant defence; its expression is rapidly up-regulated under oxidative stress, although its enhanced function increases extracellular glutamate levels and may cause excitotoxicity . Notably, system xc− is expressed by astrocytes, and by resting and activated microglia [26,44].