cAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal

Abstract

Cyclic adenosine monophosphate (cAMP) is a crucial second messenger involved in both pre- and postsynaptic plasticity in many neuronal types across species. In the hippocampal mossy fiber (MF) synapse, cAMP mediates presynaptic long-term potentiation and depression. The main cAMP-dependent signaling pathway linked to MF synaptic plasticity acts via the activation of the protein kinase A (PKA) molecular cascade. Accordingly, various downstream putative synaptic PKA target proteins have been linked to cAMP-dependent MF synaptic plasticity, such as synapsin, rabphilin, synaptotagmin-12, RIM1a, tomosyn, and P/Q-type calcium channels. Regulating the expression of some of these proteins alters synaptic release probability and calcium channel clustering, resulting in short- and long-term changes to synaptic efficacy. However, despite decades of research, the exact molecular mechanisms by which cAMP and PKA exert their influences in MF terminals remain largely unknown. Here, we review current knowledge of different cAMP catalysts and potential downstream PKA-dependent molecular cascades, in addition to non-canonical cAMP-dependent but PKA-independent cascades, which might serve as alternative, compensatory or competing pathways to the canonical PKA cascade. Since several other central synapses share a similar form of presynaptic plasticity with the MF, a better description of the molecular mechanisms governing MF plasticity could be key to understanding the relationship between the transcriptional and computational levels across brain regions.

Chemogenetic silencing reveals presynaptic Gi/o protein-mediated inhibition of synchronized activity in the developing hippocampusin vivo

“…It is important to consider that over timescales longer than those addressed in this study, G i/o -dependent actuators are anticipated to exert additional influence on canonical cAMP-protein kinase A pathways. These pathways have previously been implicated in, for instance, the synaptic incorporation of AMPA receptors (Esteban et al, 2003), postsynaptic long-term potentiation (Yasuda et al, 2003), presynaptic long-term plasticity (Sakaba and Neher, 2003; Atwood et al, 2014; Shahoha et al, 2022), synapse formation (Liang et al, 2021) as well as neuronal migration and neurite growth (Bony et al, 2013). Taken together, we demonstrate that hM4Di can serve as a valuable presynaptic silencer in mice shortly after birth.…”

Cyclic nucleotide-induced bidirectional long-term synaptic plasticity inDrosophilamushroom body

“…Conversely, low-frequency stimulation of mossy fibers induces presynaptic LTD by inactivating AC via metabotropic glutamate receptors (Tzounopoulos et al ., 1998). PKA is considered by far the most major molecule that mediates LTP/LTD at the mossy fiber terminals, and the target molecules include many active zone and vesicular proteins such as Rab3a, synapsin, RIM1a, synaptotagmin, and tomosyn (Shahoha et al ., 2022). Some of these proteins are also implicated in memory defect in Drosophila (Knapek et al ., 2010; Chen et al ., 2011; Niewalda et al ., 2015).…”

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

“…Furthermore, KD of C1ql2 in WT DGN recapitulated the Bcl11b phenotype with impaired SV recruitment and loss of LTP, supporting the specificity of C1ql2 function. MF-LTP, which manifests as a long-term increase in presynaptic vesicle release probability (P r ) (Shahoha et al, 2022), directly depends on the distribution of SV in the proximity of the AZ. Recent studies have shown that the increase in P r involves the recruitment of new AZ and an increase in the number of docked and tethered vesicles, corresponding to the readily releasable pool of SV (Orlando et al, 2021; Vandael et al, 2020).…”