Neurotransmitter receptors on microglia

Microglia are the intrinsic immune cells of the brain and express chemokine and cytokine receptors that interact with the peripheral immune cells. Recent studies have indicated that microglia also respond to the brain's classical signalling substances, the neurotransmitters. Here, we review the evidence for the expression of neurotransmitter receptors on microglia and the consequences of this receptor activation for microglial behaviour. It is evident that neurotransmitters instruct microglia to perform distinct types of responses, such as triggering an inflammatory cascade or acquiring a neuroprotective phenotype. Understanding how microglia respond to different neurotransmitters will thus have important implications for controlling the reactivity of these cells in acute injury, as well as for treating chronic neurodegenerative diseases.

Introduction

Microglia are present in all regions of the central nervous system (CNS), although their density varies in different brain regions [1]. Microglia, first described by Río- Hortega [2] and characterized by a small soma and several highly branched processes, are derived from the myelomonocytic lineage and invade the CNS tissue at both embryonic and postnatal stages (for reviews, see 3, 4). These microglial precursors possess an ameboid morphology and actively migrate within the brain parenchyma to colonize all regions of the brain. Microglia acquire a highly ramified morphology in the healthy adult brain; microglia in this form are termed ‘resting microglia’. [5]. When one observes the morphology of resting microglia, it is evident that each cell has a territory that it covers with its highly branched processes. Two recent reports have noted that these processes are highly motile; in fact, they are the most dynamic structures in the CNS 6, 7. This process movement could be viewed as a constant survey of the microglial cell's territory, and these cells should perhaps be termed ‘surveying’ than ‘resting’ microglia (Figure 1, Figure 2, Figure 3).

The majority of previous studies on microglia have been concerned with their role in pathology (for a review, see [3]). Microglia are the first elements to respond after any kind of disturbance in the brain. They undergo a transformation, also termed microglial activation, that can happen within a few hours and last many days. One feature of this activation process is the transformation of the cells into an ameboid morphology that is similar to that of the initial infiltrating precursors. Depending on the pathologic stimulus, the activated microglia might proliferate, migrate toward injured or damaged areas and/or be induced to release many factors, such as cytokines or reactive oxygen species (ROS), that affect the pathologic process. Microglia are antigen-presenting cells because they express proteins of the MHC-II complex and are, thereby, interaction partners with infiltrating T lymphocytes. They express a wide array of characteristic immune-cell receptors, such as chemokine and cytokine receptors and receptors of the complement-factor family. Thus, microglia have been viewed as intrinsic immune cells, but they have not been considered as normal communication partners within the neuronal network. Functional synapses have recently been discovered on subtypes of astrocytes [8], but there is no evidence so far to suggest that microglia might receive synaptic input.

In the following discussion, we will, however, summarize the evidence that microglia can express a variety of different classical neurotransmitter receptors that were originally thought to be specific for neurons but in the interim have been widely described in macroglial cells (astrocytes and oligodendrocytes). Synaptic structures are missing on microglia, so how can microglial transmitter receptors be activated? In 1995, Agnati and Fuxe proposed a model of ‘volume transmission’, as opposed to ‘wiring transmission’ 9, 10. In this model, neuroactive substances are not only strictly confined to the synaptic cleft but can also diffuse in the extracellular space and activate extrasynaptic receptors. Indeed, neurons express transmitter receptors not only at the postsynaptic density but also at the presynapse and other regions of the cell. It has been recognized that these extrasynaptic receptors serve many regulatory roles in the neuronal network. This makes it increasingly likely that neurotransmitter receptors are also activated on microglia because of the diffusion of transmitters in the extracellular space.