Histamine and astrocyte function

Abstract

Astrocytes support the brain through numerous functional interactions in health and disease. The recent advances in our knowledge of astrocyte involvement in various neurological disorders raised up several questions about their role and functioning in the central nervous system. From the evidence discussed in this review, we show that histamine importantly influences the main astrocytic activities such as ion homeostasis, energy metabolism, neurotransmitter clearance, neurotrophic activity and immune response. These processes are mediated through at least three histamine receptor subtypes, H₁, H₂ and H₃, expressed on the astrocyte surface. Thus, we recognize histamine as an important player in the modulation of astrocytic functions that deserves further considerations in exploring involvement of astrocytes in neurological disorders.

Introduction

Astrocytes are the most abundant non-neuronal population of cells in the central nervous system (CNS). Being assembled in highly complex networks with surrounding neurons and the cells from other germ layers (microglia, endothelial cells etc.) [1] astrocytes with heterogenous structure and function provide for fundamentals of brain homeostasis and intrinsic brain defence system [2]. During brain development, astrocytes are the central elements of neurogenesis by offering trophic support to migrating neuronal cells and guiding formation and maintenance of neural pathways, and play a role in synaptogenesis and synaptic maturation [3], [4], [5]. In the adult brain, astrocytes participate to the blood-brain barrier and blood flow control within brain [6], [7], [8]. They maintain synaptic homeostasis and intimately control the synaptic plasticity and functioning of tripartite synapse, thus regulating neuronal signalling [9], [10], [11]. Astrocytes also determine the fate of endogenous neural precursors, eliminate neurotoxins and protect neurons from oxidative damage [2], [12]. They regulate the recruitment and activity of infiltrating haematogenous cells through expression of proteases, protease inhibitors, adhesion molecules, and extracellular matrix components and contribute to the immune response in the brain through the synthesis and secretion of different cytokines and trophic factors, and thus fulfill important protective and reparative functions [2], [13], [14]. In the brain injury and/or pathological processess, astrocytes undergo morphological in physiological changes that increase their metabolic activity, needed for regenerative processes.

An intimate relationship between astrocytes and neurones appears a fundamental element of many functional interactions since by covering the majority of synapses, astrocytes are in a prime location for fostering and maintaining synaptic connectivity. A complex signalling between astrocytes and neurons on one side, and astrocytes and blood vessels on the other, enables an exchange of a huge amount of information in the CNS.

Several mechanisms have been suggested to underline the release of signalling molecules from astrocytes: reverse operation of glutamate transporters, volume-regulated anion channels, gap-junctional hemi channels, diffusional release through purinergic receptors and Ca²⁺-dependent exocytosis [2], [15], [16], [17], [18]. There is a wide range of receptors expressed on astrocytes that are functionally coupled to changes in membrane potential or to intracellular signalling pathways such as activation of phospholipase C or adenylate cyclase. Both pathways are associated with the changes of intracellular concentration of Ca²⁺ ions which allow cell-to-cell communication, typical for astrocytes. Among identified receptors such as glutamatergic, GABAergic, adrenergic, purinergic, serotonergic, muscarinic, and peptidergic receptors, which have been found on protoplasmic, fibrous, or specialized (Bergmann glia, pituicytes, Müller glia) astrocytes in situ and in vivo [13], [19]; astrocytes express also different types of histamine receptors [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. Expression of histamine receptors enables astrocytes to be an additional neuromodulatory system that encode and integrate incoming inputs of histamine from different sources. The aim of this review is to highlight our limited understanding of the involvement of histamine and histamine receptors on astroglial cell function.