Target-cell-dependent plasticity within the mossy fibre-CA3 circuit reveals compartmentalized regulation of presynaptic function at divergent release sites

Abstract

Individual axons of central neurons innervate a large number of distinct postsynaptic targets belonging to divergent functional categories such as glutamatergic principal cells and inhibitory interneurons. While each bouton along a common axon should experience the same activity pattern in response to action potential firing within the parent presynaptic neuron, accumulating evidence suggests that neighbouring boutons contacting functionally distinct postsynaptic targets regulate their release properties independently, despite being separated by only a few microns. This target-cell-specific autonomy of presynaptic function can greatly expand the computational prowess of central axons to allow for precise coordination of large neuronal ensembles within a given circuit. An excellent example of target-cell-specific presynaptic mechanisms occurs in the CA3 hippocampus where mossy fibre (MF) axons of dentate gyrus granule cells target both principal cells and local circuit inhibitory interneurons via both anatomically and functionally specialized terminals. Of particular interest, mechanisms of both short- and long-term plasticity remain autonomous at these divergent release sites due to an anatomical and biochemical segregation of discrete molecular signalling cascades. Here we review roughly a decades worth of research on the MF-CA3 pathway to showcase the target-cell dependence of presynaptically expressed NMDA receptor-independent synaptic plasticity.

Figure 1. Target-cell-specific plasticity at MF synapses

Three schematics depicting the three most common forms of non-associative, HFS-induced activity-dependent plasticity observed at MF synapses in the CA3 hippocampus. A, a non-associative HFS-induction protocol typically produces a presynaptically expressed NMDAR-independent form of LTP at CA3 pyramidal cell synapses. This HFS-induced persistent increase in release relies in part on the activation of an adenylyl cyclase (AC)–cAMP–PKA cascade in the presynaptic terminal that ultimately leads to phosphorylation of the active zone protein RIM1alpha to enhance initial releases probability independent of changes in presynaptic Ca²⁺ dynamics. B and C, at filopodial or en passant synapses onto SLINs the same induction protocol induces two forms of LTD. B, LTD at CI-AMPAR-dominated synapses has a postsynaptic locus for both induction and expression. This form of LTD is NMDAR dependent, requires an elevation of postsynaptic Ca²⁺ and relies on internalization of surface AMPARs. C, LTD at CP-AMPAR-containing synapses also requires an elevation of postsynaptic Ca²⁺ for induction but expression is presynaptic. This NMDAR-independent form of plasticity requires presynaptic mGluR7 activation which triggers a PKC- and retrograde messenger-dependent persistent inhibition of P/Q-type VGCCs leading to a reduction in glutamate release. Please note that the schematics are for illustrative purposes only and the absence of mGluR7 in the middle panel is not meant to imply that CI-AMPAR-containing MF–SLIN synapses are devoid of mGluR7. Also for simplicity of highlighting intraterminal signalling cascades, the mGluR7 and P/Q-type VGCCs are mislocalized as both should concentrate within the presynaptic active zone. Modified from Maccaferri & McBain (2008).