Transporters: a cure for synaptic depression

Synaptic transmission is a complex process that can be fine-tuned and tweaked by numerous mechanisms. Nowhere is that more true than at the mossy fibre to CA3 pyramidal cell synapse in the hippocampus. This specialized synapse, formed by the granule cell axons making en passant connections onto large multiheaded postsynaptic spines (named thorny excrescences), has a number of curious properties and is functionally regulated by several well-characterized mechanisms. Mossy fibre synapses are fundamentally different to other hippocampal synapses because the expression of long-term plasticity (both potentiation and depression) is presynaptic, requiring a long-lasting change in glutamate release probability. The almost universal acceptance that synaptic plasticity is, at least in part, a cellular correlate for learning and memory has provoked a slew of studies describing the molecules that play a role in both mediating and modulating long-term changes in synaptic efficacy. One of the primary modes by which mossy fibre synaptic transmission can be modulated is through the activation of presynaptic glutamate-activated autoreceptors. Two classes of glutamate receptor are known to be important for modulating mossy fibre synaptic transmission. Activation of the group II metabotropic glutamate receptor, mGluR2, depresses synaptic transmission and is required for the induction of mossy fibre long-term depression (LTD) (Yokoi et al. 1996). In contrast, activation of presynaptic ionotropic glutamate receptors of the kainate receptor subfamily can both facilitate and depress transmission, and contribute to mossy fibre long-term potentiation (LTP) (Contractor et al. 2001). These autoreceptors therefore represent convenient targets for modulating mossy fibre synaptic transmission and could be important for targeting hippocampal function in neurological diseases. In this issue of The Journal of Physiology Omrani and colleagues (Omrani et al. 2009) present evidence that regulating the amount of glutamate uptake can have a dramatic impact on the ability of mossy fibre synapses to express long-term depression (LTD). The authors make use of an interesting observation that some β-lactam antibiotics can transcriptionally up-regulate the expression of the glutamate transporter GLT-1, a process that might hold some promise for reducing excitotoxicity in certain neuropathologies (Rothstein et al. 2005). The authors demonstrate that the expression of GLT-1 is increased in the brains of rats which are treated with the β-lactam antibiotic ceftriaxone. GLT-1 is generally thought to be an astroglial transporter; however, more recently it has been demonstrated that it may also be expressed in neurons, and more importantly, in excitatory synaptic terminals in the hippocampus (Chen et al. 2004). In agreement with this, Omrani et al. found that immunogold particles labelled both astrocyte processes and mossy fibre terminals in the stratum lucidum. In animals that were treated with ceftriaxone the density of both cytoplasmic and membrane-associated particles was increased. The authors hypothesized that the elevated expression of glutamate transporters close to the active zones (where glutamate is released) could potentially alter the glutamate transient in the synaptic cleft during induction of synaptic plasticity and fail to activate presynaptic autoreceptors that are required for LTP or LTD. In particular, the authors focused on mossy fibre LTD and the activation of mGluR2. Indeed, the authors found that in recordings from slices from ceftriaxone-treated animals, a low-frequency stimulation protocol failed to induce LTD; however, LTD could be rescued by application of the GLT-1-selective antagonist dihydrokainate (DHK). These results indicate that it is likely that presynaptic mGluRs, which are thought to be localized somewhat distant from mossy fibre release sites, are not effectively engaged by low-frequency LTD induction protocols in ceftriaxone-treated slices probably because glutamate is more efficiently transported from the synaptic cleft (Fig. 1). Figure 1 Model of GLT-1 modulation of mossy fibre synaptic plasticity The present study describes an intriguing observation, and furthers our knowledge of mechanisms that regulate mossy fibre synaptic transmission. In particular, the novel demonstration of the contribution of glutamate transporters to mossy fibre synaptic plasticity provides a potential target for enhancing (or decreasing) synaptic plasticity. The study also raises several questions which the authors did not fully explore here. For instance, there are deficits in both frequency facilitation and mossy fibre LTP in ceftriaxone-treated animals. As stated above, ionotropic kainate receptors contribute to these forms of plasticity, so it would have been interesting to determine if, in fact, a reduction in the activation of kainate receptors underlay deficits in these forms of plasticity when GLT-1 is up-regulated. A broader question about the implication of these findings might be answered by performing behavioural studies in ceftriaxone-treated animals. Ceftriaxone is in clinical use as an antibiotic and has been proposed to be neuroprotective against excitotoxity in stroke. However, if synaptic plasticity mechanisms are also impaired by ceftriaxone one might potentially expect some impact on learning and memory. It will take future studies to work out these details, but the current cellular studies provide fascinating insight into glutamate transporters and their role in regulating synaptic transmission.