Neurotransmitter receptor heteromers and their integrative role in 'local modules': the striatal spine module

‘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 A_2A 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–A_2A 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.