Editors' ChoiceSynaptic Plasticity

Revealing a Role for Presynaptic Glutamate Receptors in LTP

Sci. Signal.  09 Dec 2014:
Vol. 7, Issue 355, pp. ec341
DOI: 10.1126/scisignal.aaa4347

Long-term changes in synaptic activity, such as long-term potentiation (LTP), represent molecular mechanisms of learning and memory. At many glutamatergic synapses, the postsynaptic NMDA-type and AMPA-type glutamate receptors are critical for LTP. Park et al. expressed a light-activated and fluorescent protein–tagged channelrhodopsin in corticostriatal neurons and then used light to trigger LTP. Synapses lacking presynaptic NMDA glutamate receptor function (targeted knockout of the gene encoding the GluN1 subunit in the same cortical neurons expressing channelrhodopsin) failed to exhibit LTP, whereas synapses with functional pre- and postsynaptic NMDA glutamate receptors exhibited LTP in response to theta burst stimulation mediated optogenetically. Targeted knockout of brain-derived neurotrophic factor (BDNF) in the channelrhodospin-expressing cortical axons also prevented light-induced LTP. Calcium signaling measured with the genetically encoded calcium sensor GCaMP5 showed that electrical theta burst stimulation induced sustained calcium signals only in control cortical axons and failed to sustain the signal when the axons lacked GluN1, indicating that presynaptic NMDA glutamate receptor activity was required. Two-photon microscopy of cortical axons expressing BDNF tagged with a pH-dependent fluorophore showed that electrical theta burst stimulation triggered the secretion of BDNF, and this secretion was blocked if the axons lacked GluN1, indicating that secretion of BDNF required presynaptic NMDA glutamate receptor activity. Not only does this study show that presynaptic NMDA receptor activity is necessary for LTP at corticostriatal synapses, it also exhibits the effectiveness of combining optogenetics with genetic knockout or targeted expression to investigate synaptic plasticity at individual synapses.

H. Park, A. Popescu, M-m. Poo, Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP. Neuron 84, 1009–1022 (2014). [PubMed]