Differential Roles of Glial and Neuronal Glutamate Transporters in Purkinje Cell Synapses

Abstract

Glutamate transporters are essential for terminating excitatory neurotransmission. Two distinct glutamate transporters, glutamateaspartate transporter (GLAST) and excitatory amino acid transporter 4 (EAAT4), are expressed most abundantly in the molecular layer of the cerebellar cortex. GLAST is expressed in Bergmann glial processes surrounding excitatory synapses on Purkinje cell dendritic spines, whereas EAAT4 is concentrated on the extrasynaptic regions of Purkinje cell spine membranes. To clarify the functional significance of the coexistence of these transporters, we analyzed the kinetics of EPSCs in Purkinje cells of mice lacking either GLAST or EAAT4. There was no difference in the amplitude or the kinetics of the rising and initial decay phase of EPSCs evoked by stimulations of climbing fibers and parallel fibers between wild-type and EAAT4-deficient mice. However, long-lasting tail currents of the EPSCs appeared age dependently in most of Purkinje cells in EAAT4-deficient mice. These tail currents were never seen in mice lacking GLAST. In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice. The results indicate that these transporters play differential roles in the removal of synaptically released glutamate. GLAST contributes mainly to uptake of glutamate that floods out of the synaptic cleft at early times after transmitter release. In contrast, the main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus prevents the transmitter from spilling over to neighboring synapses.

DrosophilaGlial Glutamate Transporter Eaat1 Is Regulated by Fringe-Mediated Notch Signaling and Is Essential for Larval Locomotion

“…Knock-out mice for only GLAST fail complex motor tasks (Watase et al, 1998). This might reflect a role for this transporter in Bergmann glia of the cerebellum, where loss of GLAST is associated with inappropriate innervation and neurotransmission at glutamatergic synapses onto Purkinje neurons (Watase et al, 1998;Marcaggi et al, 2003;Takayasu et al, 2005Takayasu et al, , 2006. The acute role in crawling that we uncovered by conditional inactivation of Eaat1 after embryogenesis supports the idea that, in Drosophila as in mice, glutamate transport strongly influences neurotransmission controlling motor function in vivo.…”

Glutamate Transporter Coupling to Na,K-ATPase

“…Glutamate transporter expression in the cerebellum is known to vary among different mammalian species. Unlike other species such as mice (Takayasu et al, 2005;Williams et al, 2005) and primates (Williams et al, 2005) in which GLAST expression is restricted to the Bergmann glia, in the rat cerebellum GLAST protein expression is present not only in the Bergmann glia but also in the granule cell layer (Chaudhry et al, 1995;Williams et al, 2005). Together, the results depicted in Figure 1 show that GLAST and ␣2 Na,KATPase are coexpressed in the Bergmann glia of the cerebellar cortex.…”

Glutamate Transporters Regulate Lesion-Induced Plasticity in the Developing Somatosensory Cortex

“…Because glutamate transporters control glutamate receptormediated synaptic transmission and plasticity (Katagiri et al, 2001;Wadiche and Jahr, 2005;Takayasu et al, 2005Takayasu et al, , 2006, we had surmised before experiments that phenotypes of glutamate transporter-defective mice might approximate those in mutant mice lacking glutamate receptors. However, whisker-related patterns were formed normally, and presynaptic and postsynaptic patterns were normally differentiated in GLT1-KO mice.…”

“…Subse-quently, GLT1 has been shown to be expressed in neuronal elements transiently during embryonic stages (Furuta et al, 1997;Yamada et al, 1998;Northington et al, 1999), although a particular splice form of GLT1 was reported to be expressed in adult brains (Chen et al, 2002(Chen et al, , 2004Schmitt et al, 2002;Berger et al, 2005). Previous reports have demonstrated physiological roles of these transporters in neuronal differentiation and survival, synaptic transmission and plasticity, and metabolic cross talk between neurons and glia Watase et al, 1998;Katagiri et al, 2001;Voutsinos-Porche et al, 2003;Takayasu et al, 2005Takayasu et al, , 2006Matsugami et al, 2006). Little is known, however, about their role in activity-dependent synapse development, through which cortical circuits attain functional and anatomical maturity Singer, 1995;Crair, 1999).…”