Abstract
A role for Wnt signal transduction in the development and maintenance of brain structures is widely acknowledged. Recent studies have suggested that Wnt signaling may be essential for synaptic plasticity and neurotransmission. However, the direct effect of a Wnt protein on synaptic transmission had not been demonstrated. Here we show that nanomolar concentrations of purified Wnt3a protein rapidly increase the frequency of miniature excitatory synaptic currents in embryonic rat hippocampal neurons through a mechanism involving a fast influx of calcium from the extracellular space, induction of post-translational modifications on the machinery involved in vesicle exocytosis in the presynaptic terminal leading to spontaneous Ca(2+) transients. Our results identify the Wnt3a protein and a member of its complex receptor at the membrane, the low density lipoprotein receptor-related protein 6 (LRP6) coreceptor, as key molecules in neurotransmission modulation and suggest cross-talk between canonical and Wnt/Ca(2+) signaling in central neurons.
Highlights
Throughout mammalian brain development Wnt signaling seems to be spatially confined to specialized regions such as the olfactory bulb, frontal cortex, hippocampal formation, and the cerebellum [1,2,3,4,5]
We show that nanomolar concentrations of purified Wnt3a protein rapidly increase the frequency of miniature excitatory synaptic currents in embryonic rat hippocampal neurons through a mechanism involving a fast influx of calcium from the extracellular space, induction of post-translational modifications on the machinery involved in vesicle exocytosis in the presynaptic terminal leading to spontaneous Ca2؉ transients
Our results identify the Wnt3a protein and a member of its complex receptor at the membrane, the low density lipoprotein receptor-related protein 6 (LRP6) coreceptor, as key molecules in neurotransmission modulation and suggest crosstalk between canonical and Wnt/Ca2؉ signaling in central neurons
Summary
Purified Wnt3a Enhances Excitatory Neurotransmission— We purified Wnt3a protein from stable mouse L-cells following standard protocols [21, 22] and consistently recovered a fully functional Wnt3a ligand that induced accumulation of its -catenin target in primary cultures of embryonic rat hippocampal neurons (12–13 DIV) (Fig. 1, A–D). We found that Wnt3a produced a concentration-dependent increase in the frequency of spontaneous synaptic currents (Fig. 2A), which at the cellular level is likely associated with an increase in the activity of the neuronal network, reflecting the sum of action potentials and synaptic potentials. Analyses of characteristic parameters of action potentials (i.e. threshold, amplitude, and duration) showed that no significant differences were found in control versus treated neurons with 10 nM Wnt3a for 15 min (Fig. 2B and Table 1). There were no significant differences in input resistance in control and Wnt3a-treated neurons (Table 1). Electrical parameters (action potentials and input resistance) recorded in hippocampal neurons in the absence or presence of Wnt3a (10 nM , 15 min). AMP, amplitude; TH, threshold; AP/2, duration of action potentials; IR, input resistance
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