Neural Circuit Development and Plasticity Shaped by Glutamate Transporters

Abstract

Glutamate receptors and ion channels that mediale Ca2+ influx and release play a critical role in the activity-dependenl pruning of immature synaptic circuitry, as shown for N-methyl-D-aspartate (NMDA) receptors in the whisker-related patterning of thalamocortical (TC) synapses and mGluR1 and P/Q-type Ca2+ channels in the elimination of surplus climbing fibers (CFs) onto cerebellar Purkinje cells (PCs). Recently we have identified unique roles played in synapse development by the glutamate transporters GLT1 and GLAST. two astrocytic transporters predominant in the cerebrum and cerebellum, respectively. In the somatosensory cortex of GLT1-knockout mice, whisker-related patterning of TC synapses and their critical period termination occurred normally in the first postnatal week. However, when a lesion was given to row-C whiskers during the critical period (postnatal days 0–3) in GLTl-knockout mice, the shrinkage of lesioned row-C barrels and the reciprocal expansion of intact row-B/D barrels were significantly diminished. Thus, GLT1 magnifies the lesion-induced plasticity of TC synapses during the critical period. In the cerebellum of GLAST-knockout mice. the territorial innervation of PC dendrites, i.e.. the innervation of proximal dendrites by CFs and distal dendrites by parallel fibers, was normally structured. However, dendritic innervation by single major CFs was significantly regressed and. instead, their aberrant wiring to neighboring PC dendrites was induced conspicuously and caused multiple innervation. This aberrant innervation was infrequent during the first 3 postnatal weeks (when surplus CFs are normally eliminated in wild-type rodents), and became progressively exacerbated thereafter. Moreover, in a similar time course, the synapseenwrapping processes of Bergmann glia were progressively retracted, resulting in incomplete glial sealing of PC synapses. Presumably through glutamate uptake and synapse-sealing functions. GLAST thus promotes and maintains CF monoinnervation by consolidating single major CFs innervating the PCs and preventing their aberrant wiring to neighboring PCs. These phenotypes collectively suggest that glutamate transporters operate as an activity discriminator in competitive synaptic wiring; with this operation, major afferents to postsynaptic targets can further expand their innervation, whereas innervation by minor afferents is diminished or suppressed. This molecular function provides neural circuits with a “winner-takes-more” strategy, by which activity-dependent remodeling is facilitated in the developing somatosensory cortex and monoinnervation by single CFs is maintained in the adult cerebellum.