Abstract
Loss of excitatory amino acid transporters (EAATs) has been implicated in a number of human diseases including spinocerebellar ataxias, Alzhiemer’s disease and motor neuron disease. EAAT4 and GLAST/EAAT1 are the two predominant EAATs responsible for maintaining low extracellular glutamate levels and preventing neurotoxicity in the cerebellum, the brain region essential for motor control. Here using genetically modified mice we identify new critical roles for EAAT4 and GLAST/EAAT1 as modulators of Purkinje cell (PC) spontaneous firing patterns. We show high EAAT4 levels, by limiting mGluR1 signalling, are essential in constraining inherently heterogeneous firing of zebrin-positive PCs. Moreover mGluR1 antagonists were found to restore regular spontaneous PC activity and motor behaviour in EAAT4 knockout mice. In contrast, GLAST/EAAT1 expression is required to sustain normal spontaneous simple spike activity in low EAAT4 expressing (zebrin-negative) PCs by restricting NMDA receptor activation. Blockade of NMDA receptor activity restores spontaneous activity in zebrin-negative PCs of GLAST knockout mice and furthermore alleviates motor deficits. In addition both transporters have differential effects on PC survival, with zebrin-negative PCs more vulnerable to loss of GLAST/EAAT1 and zebrin-positive PCs more vulnerable to loss of EAAT4. These findings reveal that glutamate transporter dysfunction through elevated extracellular glutamate and the aberrant activation of extrasynaptic receptors can disrupt cerebellar output by altering spontaneous PC firing. This expands our understanding of disease mechanisms in cerebellar ataxias and establishes EAATs as targets for restoring homeostasis in a variety of neurological diseases where altered cerebellar output is now thought to play a key role in pathogenesis.
Highlights
Excitatory amino acid transporter 4 (EAAT4) and GLAST/EAAT1 are members of a family of five sodium-dependent plasma membrane glutamate transporters (EAATs) [1] and are the major glutamate transporters in the cerebellum, the region of the brain essential for maintaining postural control and coordination of voluntary muscle movement [2]
We demonstrate for the first time that the two predominant cerebellar glutamate transporters, EAAT4 and GLAST/EAAT1, have critical but differential roles in the modulation of spontaneous Purkinje cell (PC) firing patterns
In contrast GLAST/EAAT1 appears to play no role in modulating the firing pattern of the Zþ subpopulation of PCs but it does have a fundamental role in sustaining normal spontaneous simple spike activity in low EAAT4 expressing (Z–) PCs by preventing NMDA receptor activation
Summary
Excitatory amino acid transporter 4 (EAAT4) and GLAST/EAAT1 (rodent/human nomenclature) are members of a family of five sodium-dependent plasma membrane glutamate transporters (EAATs) [1] and are the major glutamate transporters in the cerebellum, the region of the brain essential for maintaining postural control and coordination of voluntary muscle movement [2]. EAAT4 displays a differential pattern of expression within parasagittal bands, mapping onto that of aldolase C (zebrin II), with zebrin-positive (Zþ) PCs expressing EAAT4 to a much higher level than zebrin-negative (Z–) PCs [27,28] This variable EAAT4 density has been shown to have synaptic physiological consequences with larger glial AMPAR-mediated current amplitudes observed in regions where PCs have lower endogenous levels of EAAT4 [29] and the synaptic activation of mGluR1a, which exhibits the same peri-synaptic distribution as EAAT4 [28,30], found to be dampened in regions of high EAAT4 expression despite no differential expression of mGluR1a [31]. Instead it is the density of EAATs that governs the rapidity of binding and sequestration of glutamate after synaptic release [33]
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