Ectopic release of glutamate contributes to spillover at parallel fibre synapses in the cerebellum. (13th February 2014)

• Record Type: Journal Article
• Authors: Balakrishnan, Saju; Dobson, Katharine L.; Jackson, Claire; Bellamy, Tomas C.
• Is Part Of: Journal of physiology. Volume 592:Number 7(2014:Apr.)
• Page Start: 1493
• Page End: 1503
• Publication Date: 2014-02-13
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.267039
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6051-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6051-list-0001" list-type="bullet"> <list-item> <p>Release of neurotransmitter can sometimes occur outside of the synaptic cleft, a process known as ectopic release.</p> </list-item> <list-item> <p>Spillover of the excitatory transmitter glutamate between synapses occurs when parallel fibres in the cerebellum are stimulated at high frequencies.</p> </list-item> <list-item> <p>We investigated the effect of activity‐dependent and pharmacological reduction of ectopic release on the time course of postsynaptic currents and found that the decay time is reduced, suggesting that ectopic release contributes to spillover at the synapses.</p> </list-item> <list-item> <p>This finding suggests that ectopic transmission can cause activation of extrasynaptic receptors even at low frequencies, and so may play a significant role in synaptic plasticity.</p> </list-item> <list-item> <p>The results help us understand how signalling in and around the synapse can alter network activity in the cerebellum, a brain region essential for fine motor coordination.</p> </list-item> </list> </p> </sec> <sec id="tjp6051-sec-0020" sec-type="section"> <title>Abstract</title> <p>In the rat cerebellar molecular layer, spillover of glutamate between parallel fibre synapses can lead to activation of perisynaptic receptors that mediate short‐ and long‐term plasticity. This effect is greatest when clusters of fibres are stimulated at high frequencies, suggesting that glutamate clearance mechanisms must be overwhelmed before spillover can occur. However, parallel fibres can also release transmitter directly into the extracellular space, from 'ectopic' release sites. Ectopic transmission activates AMPA receptors on the Bergmann glial cell processes that envelop parallel fibre synapses, but the possible contribution of this extrasynaptic release to intersynaptic communication has not been explored. We exploited long‐term depression of ectopic transmission, and selective pharmacology, to investigate the impact of these release sites on the time course of Purkinje neuron excitatory postsynaptic currents (EPSCs). Depletion of ectopic release pools by activity‐dependent long‐term depression decreased EPSC decay time, revealing a 'late' current that is present when fibres are stimulated at low frequencies. This effect was enhanced when glutamate transporters were inhibited, and reduced when extracellular diffusion was impeded. Blockade of N‐type Ca<sup>2+</sup> channels inhibited ectopic transmission to Bergmann glia and decreased EPSC decay time. Similarly, perfusion of the Ca<sup>2+</sup> chelator EGTA‐AM into the slice progressively eliminated ectopic transmission to glia and decreased EPSC decay time with closely similar time courses. Collectively, this evidence suggests that ectopically released glutamate contributes to spillover transmission, and that ectopic release therefore degrades the spatial precision of synapses that fire infrequently, and may make them more prone to exhibit plasticity.</p> </sec> </abstract>