Cooperation of taurine uptake and dopamine D1 receptor activation facilitates the induction of protein synthesis-dependent late LTP

Highlights

• Neurotransmitters cooperate to promote the conversion of early-LTP into late-LTP.

• Protein synthesis is fundamental for late-LTP induction.

• Taurine uptake and D1R activation facilitates late-LTP induction.

• Different signalling pathways contribute to transform early-LTP into late-LTP.

• Taurine uptake cooperates with NMDAR and D1R activation in the induction of late-LTP.

Abstract

Co-activation of NMDA and dopamine receptors is required for the induction of the late phase of LTP (L-LTP) that is dependent on new protein synthesis. Other neuromodulatory substances may also contribute to this process. Here, we examined whether taurine is one of the neuromodulators contributing to L-LTP induction, since it is known that taurine uptake induces a long-lasting synaptic potentiation dependent on protein synthesis, and taurine uptake inhibition blocks L-LTP induced by tetanization. Experiments were conducted using rat hippocampal slices where field synaptic potentials were evoked and recorded in CA3-CA1 synapses. Taurine (1 mM) applied 10 min before a high frequency stimulation (HFS) train converted a transitory early-LTP (E-LTP) into an L-LTP dependent on protein synthesis. This taurine effect was blocked by a taurine uptake inhibitor. A facilitation of L-LTP induction was also obtained by pre-application of SKF38393, a D1/D5 dopamine receptor (D1R) agonist. In this case, LTP facilitation was not affected by the taurine uptake inhibitor. Nevertheless, when taurine and SKF38393 were simultaneously pre-applied at a concentration that individually did not modify E-LTP, they produced a synergistic mechanism that facilitated the induction of L-LTP with a sole HFS train. This facilitation of L-LTP was blocked by inhibiting either taurine uptake or D1R activation. Taurine and SKF38393 activated different signaling pathways to transform E-LTP into L-LTP. Taurine-induced L-LTP facilitation required MAPK activation, while D1R-agonist-induced facilitation depended mainly on PKA activation and partially on MAPK activation. On the other hand, the synergistic mechanisms induced by the cooperative action of taurine and SKF38393 were impaired by inhibitors against MAPK, PKA and PI3-K. This pharmacological profile resembles that displayed by L-LTP induced by three HFS trains at 10-min intervals. These results indicate that taurine uptake is necessary and cooperates with other neurotransmitter systems in the induction of L-LTP.

Introduction

Long-term changes in synaptic efficacy are widely used to gain insight into the cellular basis of learning and memory processes. The direction, magnitude and duration of such synaptic modifications depend on the pattern of synaptic stimulation applied, as different stimulation patterns activate different signaling pathways. For example, the protein synthesis-dependent phase of long-term potentiation (L-LTP) is usually evoked by three to four high frequency trains of synaptic stimuli (HFS) spaced 5–10 min apart (Kandel, 2001). A number of studies have demonstrated that L-LTP induction in the hippocampal CA1 region requires dopamine D1R activation (Frey et al., 1991, Huang and Kandel, 1995, Swanson-Park et al., 1999, Granado et al., 2008), and that this type of receptor has to be co-activated with NMDA receptors to be effective (O'Carroll and Morris, 2004, Navakkode et al., 2007, Stramiello and Wagner, 2008). In addition, other neuromodulatory molecules such as noradrenaline, brain-derived neurotrophic factor and nitric oxide (Bailey et al., 2000) might contribute to the coordination of the different signaling pathways involved in the transition from an early phase of LTP (E-LTP) to a more perdurable potentiation phenomenon. However, the exact identity of these neuromodulators and their interactions resulting in L-LTP have not been elucidated.

We found that taurine, a natural amino acid acting as a GABA_A and glycine receptor agonist, when applied to rat hippocampal slices, induced a long-lasting potentiation of synaptic efficacy in the CA1 area, by a process independent of the activation of these receptor types (Galarreta et al., 1996). Moreover, LLT-TAU induction was also independent of NMDAR activation (Galarreta et al., 1996, Chepkova et al., 2002). In fact, taurine did not seem to activate glycine site on postsynaptic NMDAR (Suárez and Solís, 2006). Later studies revealed that taurine-induced potentiation requires a taurine uptake process (Sergeeva et al., 2003, del Olmo et al., 2004), which somehow triggers several mechanisms similar to those involved in the maintenance of L-LTP, such as PKA activation and de novo protein synthesis (del Olmo et al., 2003). We previously described that L-LTP induced with multiple high frequency trains of synaptic stimulation was impaired in the presence of an inhibitor of taurine uptake, and this blockade was overcome when the inhibitor was concomitantly applied with taurine (del Olmo et al., 2004). These results demonstrate the possibility that taurine is a key activator of the mechanisms required for L-LTP. Here, we report that pre-application of either taurine before a sole HFS train, which by itself only induces E-LTP, causes a perdurable L-LTP requiring protein synthesis.