The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory

The brain renin-angiotensin system (RAS) has long been known to regulate several classic physiologies including blood pressure, sodium and water balance, cyclicity of reproductive hormones and sexual behaviors, and pituitary gland hormones. These physiologies are thought to be under the control of the angiotensin II (AngII)/AT(1) receptor subtype system. The AT(2) receptor subtype is expressed during fetal development and is less abundant in the adult. This receptor appears to oppose growth responses facilitated by the AT(1) receptor, as well as growth factor receptors. Recent evidence points to an important contribution by the brain RAS to non-classic physiologies mediated by the newly discovered angiotensin IV (AngIV)/AT(4) receptor subtype system. These physiologies include the regulation of blood flow, modulation of exploratory behavior, and a facilitory role in learning and memory acquisition. This system appears to interact with brain matrix metalloproteinases in order to modify extracellular matrix molecules thus permitting the synaptic remodeling critical to the neural plasticity presumed to underlie memory consolidation, reconsolidation, and retrieval. There is support for an inhibitory influence by AngII activation of the AT(1) subtype, and a facilitory role by AngIV activation of the AT(4) subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning. The discovery of the AT(4) receptor subtype, and its facilitory influence upon learning and memory, suggest an important role for the brain RAS in normal cognitive processing and perhaps in the treatment of dysfunctional memory disease states. (C) 2004 Elsevier Ltd. All rights reserved.