Review
Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: The striatal spine module

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Abstract

‘Local module’ is a fundamental functional unit of the central nervous system that can be defined as the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit. This review focuses on the importance of neurotransmitter receptor heteromers for the operation of local modules. To illustrate this, we use the striatal spine module (SSM), comprised of the dendritic spine of the medium spiny neuron (MSN), its glutamatergic and dopaminergic terminals and astroglial processes. The SSM is found in the striatum, and although aspects such as neurotransmitters and receptors will be specific to the SSM, some general principles should apply to any local module in the brain. The analysis of some of the receptor heteromers in the SSM shows that receptor heteromerization is associated with particular elaborated functions in this local module. Adenosine A2A receptor–dopamine D2 receptor–glutamate metabotropic mGlu5 receptor heteromers are located adjacent to the glutamatergic synapse of the dendritic spine of the enkephalin MSN, and their cross-talk within the receptor heteromers helps to modulate postsynaptic plastic changes at the glutamatergic synapse. A1 receptor–A2A receptor heteromers are found in the glutamatergic terminals and the molecular cross-talk between the two receptors in the heteromer helps to modulate glutamate release. Finally, dopamine D2 receptor–non-α7 nicotinic acetylcholine receptor heteromers, which are located in dopaminergic terminals, introduce the new concept of autoreceptor heteromer.

Introduction

Computation in the central nervous system (CNS) can be performed at various levels. Form higher to lower magnification, these levels have been identified as ‘neuronal networks’, ‘neurons’, ‘local circuits’ and ‘molecular networks’. Neuronal networks are made of assemblies of neurons that carry out specific functions (Laughlin and Sejnowski, 2003, Buzsaki and Draguhn, 2004, Tsodyks and Gilbert, 2004). The neuronal level of computation has been classically viewed as the summing up of synaptic inputs and the initiation of an action potential when a threshold is reached. However, linear and nonlinear mechanisms in the dendritic tree also play a role in the overall computation performed by the neuron (London and Hausser, 2004). Local circuit has been defined as “any portion of the neuron (or neurons) that, under given conditions, functions as an independent integrative unit” (Goldman-Rakic, 1975). However, this definition is too broad as a particular local circuit could overlap or be part of another local circuit. It is also too restrictive as it does not include glial cells, which participate in neuronal processing (Fields and Stevens-Graham, 2002). Furthermore, the word ‘circuit’ implies direct ‘wired pathways’ and extrasynaptic neurotransmission (‘volume transmission’) plays an important role at this level of computation (see below). Therefore, we use the term ‘local module’ to define the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit.

Molecular networks are made of biomolecules (especially proteins) that are functionally interconnected and can elaborate and transmit information (Xia et al., 2004). Especially relevant for this review are molecular networks that contain protein complexes localized in the plane of the membrane, the so-called ‘horizontal molecular networks’, which include ‘neurotransmitter receptor heteromers’ (Agnati et al., 2003, Agnati et al., 2005, Franco et al., 2003). In this review the term neurotransmitter is used as defined by Snyder and Ferris (2000), i.e. a molecule, released by neurons or glia, which physiologically influences the electrochemical state of adjacent cells. This definition includes previous ill-defined terms, such as neuromodulator, neuropeptide and also gaseous messenger, such as nitric oxide and carbon monoxide. In order to understand the integrative capabilities of the CNS, we must consider both the spatial–temporal relationships among informational elements within a certain computational level and the spatial–temporal relationships among computations carried out at the different levels. This functional hierarchical organization of the computational devices in the CNS raises the question of how information circulates among the different levels. As it will be shown in this review, neurotransmitter receptor heteromers are functional units of special relevance since they act as a ‘bridge’ between the molecular networks and the local module levels of computation.

It is often assumed that communication between neurons just takes place in the synapse, where only one type of neurotransmitter is released to stimulate receptors for that neurotransmitter localized in the synapse. Several assumptions of those classical ideas are wrong. Neurons can release more that one type of biochemical signal (Hokfelt et al., 2000) and neurotransmitters can spill over from the synaptic cleft or be released from asynaptic varicosities and stimulate extrasynaptic receptors. This implies a diffuse mode of extrasynaptic neurotransmission, also called ‘volume transmission’ (Fuxe and Agnati, 1991, Nicholson and Sykova, 1998, Agnati and Fuxe, 2000, Vizi et al., 2004, Bach-y-Rita, 2005). While we would expect to find receptor heteromers in the synaptic space, it is in the extrasynaptic space where we should find most receptor heteromers that are targeted by different neurotransmitters. Although the distance that a neurotransmitter or neuromodulator can cover in the extrasynaptic space is a matter of debate (Fuxe and Agnati, 1991, Nicholson and Sykova, 1998, Agnati and Fuxe, 2000, Vizi et al., 2004, Bach-y-Rita, 2005), volume transmission must have its maximal expression in the perisynaptic space (both at the pre- and postsynaptic sites) and in the vicinity of the asynaptic varicosities. Therefore, volume transmission and neurotransmitter receptor heteromers are important variables for the computation of local modules. This review focuses on the importance of neurotransmitter receptor heteromers for the operation of local modules. To illustrate this, we use the striatal spine module (SSM). This module is found in the striatum, and although aspects such as neurotransmitters and receptors will be specific to the SSM, some general principles should apply to any local module in the brain.

Section snippets

Structural elements of the SSM

The striatal efferent neuron, also called the medium spiny neuron (MSN), constitutes more than 95% of the striatal neuronal population (Smith and Bolam, 1990, Gerfen, 2004). It is an inhibitory neuron that uses γ-aminobutiric acid (GABA) as its main neurotransmitter. In addition, there are different types of inhibitory interneurons which also use GABA and large cholinergic interneurons (Smith and Bolam, 1990, Gerfen, 2004). There are two subtypes of MSN, which selectively express one of two

General considerations

Neurotransmitters and neuromodulators at the synaptic cleft, and those that spill over from the synaptic cleft or asynaptic varicosities, encounter a variety of receptors located synaptically and extrasynaptically. It is now accepted that receptors can occur as homo-oligomers or hetero-oligomers (Bouvier, 2001, Agnati et al., 2003, Agnati et al., 2005, Franco et al., 2003, Prinster et al., 2005). Whereas homo-oligomerization does not change much our concept of neuroregulation, receptor

Conclusions and perspectives

The SSM provides an example of the impressive degree of computation that takes place in local modules. This depends on the different modes of communication (synaptic and volume transmission) used by neurotransmitters (dopamine, glutamate, acetylcholine and adenosine) and on the existence of receptor heteromers. The analysis of some of these receptor heteromers shows that receptor heteromerization is associated with particular elaborated functions in the local module. In the SSM, A2AR–D2R and A2A

Acknowledgments

Supported by the Intramural Research funds of the National Institute on Drug Abuse, NIH and grants from Spanish “Ministerio de Ciencia y Tecnología” (SAF2005-00903 to F. C. and SAF2006-05481 to R. F.) and the Swedish Research Council (K2006-04X-00715-42-2).

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