A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is co-localized with δ-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses

Abstract

Confocal immunofluorescence microscopy showed strong monocarboxylate transporter 2 (MCT2) labeling of Purkinje cell bodies and punctate labeling in the molecular layer. By immunogold cytochemistry, it could be demonstrated that the MCT2 immunosignal was concentrated at postsynaptic densities of parallel fiber-Purkinje cell synapses. The distribution of MCT2 transporters within the individual postsynaptic densities mimicked that of the delta2 glutamate receptor, as shown by use of two different gold-particle sizes. The MCT2 distribution was also compared with the distributions of other monocarboxylate transporters (MCT1 and MCT4). The MCT1 immunolabeling was localized in the endothelial cells, while MCT4 immunogold particles were associated with glial profiles, including those abutting the synaptic cleft of the parallel fiber-spine synapses. The postsynaptic density (PSD) molecules identified so far can be divided into five classes: receptors, their anchoring molecules, molecules involved in signal transduction, ion channels, and attachment proteins. Here, we provide evidence that this list of molecules must now be extended to comprise an organic molecule transporter: the monocarboxylate transporter MCT2. The present data suggest that MCT2 has specific transport functions related to the synaptic cleft and that this transporter may allow an influx of lactate derived from perisynaptic glial processes. The expression of MCT2 in synaptic membranes may allow energy supply to be tuned to the excitatory drive.

Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics

“…Commensurate with this model, monocarboxylate (including lactate) transporters have been found on neurons and astrocytes both in vitro and in vivo. Neurons primarily express the monocarboxylate transporter MCT2 (Bergersen et al, 2001;Pierre et al, 2002;Debernardi et al, 2003), the kinetics of which favor lactate uptake, whereas astrocytes express either MCT1 or MCT4 (Pierre et al, 2000;Bergersen et al, 2001;Debernardi et al, 2003), the kinetics of which favor lactate release, which is consistent with the lactate shuttle model. This lactate shuttle is stimulated during excitotoxic insults by increased concentrations of glutamate in the extracellular space.…”

<b>Cellular distributions of monocarboxylate transporters: a r</b><b>eview </b>

“…MCT3 has been localized exclusively in the retinal pigment epithelium. On the other hand, low affinity MCT4 is particularly evident in tissues with higher glycolytic rates, such as white skeletal muscle (158) and astrocytes (7,120). Its characteristics suggest an adaptation to the release of lactate in glycolytic cells.…”

“…Nevertheless, in situ hybridization analyses of the mouse brain have characterized the neuronal expression of MCT2 in the cerebral cortex, hippocampus, and cerebellar cortex, including the Purkinje cell layer (81,106,154). Another immunostaining study of the rat brain for MCT2 has detected positive reactivities of neurons in the hippocampus, thalamus, olfactory bulb, and cerebellum (7,110,120). In accordance with this, an analysis of primary cultured cells gave evidence of a cellspecific localization of MCTs with an enrichment of MCT1 in astrocytes and of MCT2 in neurons (11), though another similar analysis of the rat brain has shown that all cultured cortical astrocytes express MCT2 as well as MCT1 (57).…”

“…Accumulating evidence indicates that part of the MCT2 expression is associated with synapses. Some studies have focused on the MCT2 localization along the post-synaptic density of excitatory synapses (7,8). The major role in the post-synaptic density has been related to the maintenance of energy substrate availability upon excitation of post-synaptic cells (8).…”

“…MCT4 is present in astrocytes and involved in lactate shuttling from glia to neurons expressing MCT2. MCT4 is preferentially expressed in astrocytes including the astrocytic processes that ensheath the synapse and blood vessels (7,120) although the immunolabeling is also restricted to some regions and not so intense in reaction. It has been described how SMCTs are expressed in the brain and retina (93).…”