Stable Mossy Fiber Long-Term Potentiation Requires Calcium Influx at the Granule Cell Soma, Protein Synthesis, and Microtubule-Dependent Axonal Transport

Abstract

The synapses formed by the mossy fiber (MF) axons of hippocampal dentate gyrus granule neurons onto CA3 pyramidal neurons exhibit an intriguing form of experience-dependent synaptic plasticity that is induced and expressed presynaptically. In contrast to most other CNS synapses, long-term potentiation (LTP) at the MF-CA3 synapse is readily induced even during blockade of postsynaptic glutamate receptors. Furthermore, blocking voltage-gated Ca 2ϩ channels prevents MF-LTP, supporting an involvement of presynaptic Ca 2ϩ signaling via voltage-gated Ca 2ϩ channels in MF-LTP induction. We examined the contribution of activity in both dentate granule cell somata and MF terminals to MF-LTP. We found that the induction of stable MF-LTP requires tetanization-induced action potentials not only at MF boutons, but also at dentate granule cell somata. Similarly, blocking Ca 2ϩ influx via voltage-gated Ca 2ϩ channels only at the granule cell soma was sufficient to disrupt MF-LTP. Finally, blocking protein synthesis or blocking fast axonal transport mechanisms via disruption of axonal tubulin filaments resulted in decremental MF-LTP.Collectively, these data suggest that-in addition to Ca 2ϩ influx at the MF terminals-induction of MF synaptic plasticity requires action potential-dependent Ca 2ϩ signaling at granule cell somata, protein synthesis, and fast axonal transport along MFs. A parsimonious interpretation of these results is that somatic activity triggers protein synthesis at the soma; newly synthesized proteins are then transported to MF terminals, where they contribute to the stabilization of MF-LTP. Finally, the present data imply that synaptic plasticity at the MF-CA3 synapse can be affected by local modulation of somatic and presynaptic Ca 2ϩ channel activity.

Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release

“…In contrast, mammalian axons are much smaller and therefore more difficult to access. Previous research in rodents has so far relied on non-physiological treatments such as axotomy or non-specific manipulations such as blocking postsynaptic protein synthesis to infer a role for presynaptic translation during long-term plasticity (Barnes et al, 2010; Calixto et al, 2003; Hagena and Manahan-Vaughan, 2013; Huang and Hsu, 2004; Huang et al, 1994; Kelly et al, 2000; Yin et al, 2006). Protein synthesis can be upregulated in response to injury or occur in neighboring neurons or glia.…”

Deceivingly dynamic: Learning-dependent changes in stathmin and microtubules

“…For example, applying a microtubule-stabilizing drug, paclitaxel, leads to LTP deficits in the cortico-amygdala pathway in mouse brain slices (Shumyatsky et al, 2005). Also, an inhibitor of microtubule dynamics, nocodazole, decreases mossy fiber LTP (Barnes et al, 2010) and Schaffer collateral LTP (Jaworski et al, 2009). Since drug interfering with microtubule dynamics affect LTP, it is likely that microtubules are also involved in memory formation.…”

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

“…Hence, it is improbable that DG output relies on convergent drive from GCs and the high strength of GC-CA3 pyramidal neuron synapses may represent a necessary feature to allow the DG to robustly influence CA3. Moreover, potentiation of large mossy terminal synapses occurs in a GC autonomous fashion (i.e., is independent of the firing of other GCs or the target cell [Nicoll and Schmitz 2005;Barnes et al 2010]). …”