Activity-Dependent Upregulation of Presynaptic Kainate Receptors at Immature CA3–CA1 Synapses

Abstract

Presynaptic kainate-type glutamate receptors (KARs) regulate glutamate release probability and short-term plasticity in various areas of the brain. Here we show that long-term depression (LTD) in the area CA1 of neonatal rodent hippocampus is associated with an upregulation of tonic inhibitory KAR activity, which contributes to synaptic depression and causes a pronounced increase in short-term facilitation of transmission. This increased KAR function was mediated by high-affinity receptors and required activation of NMDA receptors, nitric oxide (NO) synthetase, and postsynaptic calcium signaling. In contrast, KAR activity was irreversibly downregulated in response to induction of long-term potentiation in a manner that depended on activation of the TrkB-receptor of BDNF. Both tonic KAR activity and its plasticity were restricted to early stages of synapse development and were lost in parallel with maturation of the network due to ongoing BDNF-TrkB signaling. These data show that presynaptic KARs are targets for activity-dependent modulation via diffusible messengers NO and BDNF, which enhance and depress tonic KAR activity at immature synapses, respectively. The plasticity of presynaptic KARs in the developing network allows nascent synapses to shape their response to incoming activity. In particular, upregulation of KAR function after LTD allows the synapse to preferentially pass high-frequency afferent activity. This can provide a potential rescue from synapse elimination by uncorrelated activity and also increase the computational dynamics of the developing CA3-CA1 circuitry.

Activity‐dependent plasticity of presynaptic GABAB receptors at parallel fiber synapses

“…A handful of reports describe activity‐dependent plasticity of other types of presynaptic receptors. Presynaptic kainate receptors are upregulated during long‐term depression (LTD) at Schaffer collateral synapses, though this was only observed at immature synapses (Clarke, Molchanova, Hirvonen, Taira, & Lauri, ). Presynaptic inhibition through cannabinoid receptors is down regulated at basket cell synapses in the hippocampus during high‐frequency (20 Hz) activity (Földy, Neu, Jones, & Soltesz, ), though this appears to be due to changes in presynaptic voltage‐gated calcium channels rather than the receptor itself.…”

Axonal Kainate Receptors Modulate the Strength of Efferent Connectivity by Regulating Presynaptic Differentiation

“…KARs influence neurite outgrowth and morphological maturation of neurons ( Ibarretxe et al, 2007 ; Joseph et al, 2011 ; Marques et al, 2013 ), regulate mobility of the axonal filopodia ( Chang and De Camilli, 2001 ; Tashiro et al, 2003 ) and mobilization of the synaptic vesicles in the growth cones ( Gelsomino et al, 2013 ). At the stage when a synaptic connection is formed and is already functional, presynaptic KARs are tonically active and inhibit vesicle release; this G-protein dependent signaling regulates the short-term dynamics of transmission ( Lauri et al, 2006 ; Clarke et al, 2014 ) and is suggested to have an important role in activity-dependent fine-tuning of the connectivity in the hippocampus ( Lauri and Taira, 2011 ).…”

Long‐term depression of presynaptic cannabinoid receptor function at parallel fibre synapses

“…; Clarke et al . ; Orts‐Del'Immagine & Pugh, ). Many synapses in the central nervous system, including parallel fibres, express a wide range of presynaptic ionotropic and metabotropic receptors; it will be interesting to determine whether other classes of receptors in other brain regions also experience activity‐dependent plasticity.…”

“…Given the high Cb1 receptor expression at parallel fibre synapses (Herkenham et al 1990;Tsou et al 1998) and that receptor plasticity is generally bidirectional, the physiological mechanisms that up-regulate Cb1 receptor function also remain to be uncovered. The field of presynaptic receptor plasticity is still new, with relatively few examples using physiological stimuli (Lauri et al 2001;Clarke et al 2014;Orts-Del'Immagine & Pugh, 2018). Many synapses in the central nervous system, including parallel fibres, express a wide range of presynaptic ionotropic and metabotropic receptors; it will be interesting to determine whether other classes of receptors in other brain regions also experience activity-dependent plasticity.…”