Signaling and gene expression in the neuron-glia unit during brain function and dysfunction: Holger Hyden in memoriam

Holger Hyden demonstrated almost 40 years ago that learning changes the bas e composition of nuclear RNA, i.e. induces an alteration in gene expression . An equally revolutionary observation at that time was that a base change occurred in both neurons and glia. From these findings, Holger Hyden conclu ded that establishment of memory is correlated with protein synthesis, and he demonstrated de novo synthesis of several high-molecular protein species after learning. Moreover, the protein, S-100, which is mainly found in gli al cells, was increased during learning, and antibodies towards this protei n inhibited memory consolidation. S-100 belongs to a family of Ca2+-binding proteins, and Holger Hyden at an early point realized the huge importance of Ca2+ in brain function. He established that glial cells show more marked and earlier changes in RNA composition in Parkinson's disease than neurons . Holger Hyden also had the vision and courage to suggest that "mental dise ases could as well be thought to depend upon a disturbance of processes in glia cells as in the nerve cells", and he showed that antidepressant drugs cause profound changes in glial RNA. The importance of Holger Hyden's findi ngs and visions can only now be fully appreciated. His visionary concepts o f the involvement of glia in neurological and mental illness, of learning b eing associated with changes in gene expression, and of the functional impo rtance of Ca2+-binding proteins and Ca2+ are presently being confirmed and expanded by others. This review briefly summarizes highlights of Holger Hyd en's work in these areas, followed by a discussion of recent research, conf irming his findings and expanding his visions. This includes strong evidenc e that glial dysfunction is involved in the development of Parkinson's dise ase, that drugs effective in mood disorders alter gene expression and exert profound effects on astrocytes, and that neuronal-astrocytic interactions in glutamate signaling, NO synthesis, Ca2+ signaling, beta -adrenergic acti vity, second messenger production, protein kinase activities, and transcrip tion factor phosphorylation control the highly programmed events that carry the memory trace through the initial, signal-mediated short-term and inter mediate memory stages to protein synthesis-dependent long-term memory. (C) 2001 Elsevier Science Ltd. All rights reserved.