Research ArticleNeuroscience

BDNF increases synaptic NMDA receptor abundance by enhancing the local translation of Pyk2 in cultured hippocampal neurons

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Science Signaling  18 Jun 2019:
Vol. 12, Issue 586, eaav3577
DOI: 10.1126/scisignal.aav3577

An RNA binding protein in synaptic plasticity

Changes in neuronal activity, such as in response to the neurotrophin BDNF, occur partly through changes to the protein composition at the neuronal synapse. Afonso et al. found that the RNA binding protein hnRNP K was critical for the synaptic synthesis of the kinase PYK2 in hippocampal neurons upon BDNF stimulation. This synaptic localization of PYK2, in turn, promoted the formation and synaptic integration of GluN2B-containing NMDA receptors, which is important for the synaptic plasticity that underlies learning and memory formation. These findings not only pinpoint a critical kinase in the broader synaptic proteome for this phenomenon but also place an RNA binding protein at the core of its regulation.


The effects of brain-derived neurotrophic factor (BDNF) in long-term synaptic potentiation (LTP) are thought to underlie learning and memory formation and are partly mediated by local protein synthesis. Here, we investigated the mechanisms that mediate BDNF-induced alterations in the synaptic proteome that are coupled to synaptic strengthening. BDNF induced the synaptic accumulation of GluN2B-containing NMDA receptors (NMDARs) and increased the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) in cultured rat hippocampal neurons by a mechanism requiring activation of the protein tyrosine kinase Pyk2 and dependent on cellular protein synthesis. Single-particle tracking using quantum dot imaging revealed that the increase in the abundance of synaptic NMDAR currents correlated with their enhanced stability in the synaptic compartment. Furthermore, BDNF increased the local synthesis of Pyk2 at the synapse, and the observed increase in Pyk2 protein abundance along dendrites of cultured hippocampal neurons was mediated by a mechanism dependent on the ribonucleoprotein hnRNP K, which bound to Pyk2 mRNA and dissociated from it upon BDNF application. Knocking down hnRNP K reduced the BDNF-induced synaptic synthesis of Pyk2 protein, whereas its overexpression enhanced it. Together, these findings indicate that hnRNP K mediates the synaptic distribution of Pyk2 synthesis, and hence the synaptic incorporation of GluN2B-containing NMDARs, induced by BDNF, which may affect LTP and synaptic plasticity.

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