Cellular factors controlling neuronal vulnerability in the brain - A lesson from the striatum

In many acute and chronic neurologic disorders, both deficits in energy met abolism and defects in glutamate-mediated excitatory synaptic transmission have been proposed as important pathogenic factors. Brain cells, however, e xpress variable vulnerability to these insults, as indicated by the fact th at certain brain areas and even different cell types in the same area are p referentially spared until the very late stages of various diseases. This c an be clearly seen in the striatum, where GABAergic projection cells but no t cholinergic interneurons are precociously damaged in the course of both a cute metabolic insults (such as hypoxia, hypoglycemia, and ischemia) and ch ronic neurodegenerative disorders (such as Huntington's disease). A well-ma pped pattern of cell loss, in fact, is a common finding in the striatum of patients suffering from these pathologic conditions. Physiologic and molecu lar studies have been directed in recent years to the identification of the cellular mechanisms underlying the cell-type specific vulnerability of str iatal cells. These studied recognized that, in striatal spiny and aspiny ce lls, specific membrane ion channels, glutamate receptor subtypes and subuni ts, and intracellular enzymatic activities are involved in the cascade of e vents responsible for opposite responses and vulnerabilities to oxygen or g lucose deprivation and to glutamate receptor-mediated toxicity. Specific mo lecules able to target these cellular factors might be employed as therapeu tic agents during acute and chronic neurologic disorders affecting this bra in area.