Bassoon controls synaptic vesicle release via regulation of presynaptic phosphorylation and cAMP

Abstract

Neuronal presynaptic terminals contain hundreds of neurotransmitter‐filled synaptic vesicles (SVs). The morphologically uniform SVs differ in their release competence segregating into functional pools that differentially contribute to neurotransmission. The presynaptic scaffold bassoon is required for neurotransmission, but the underlying molecular mechanisms are unknown. We report that glutamatergic synapses lacking bassoon feature decreased SV release competence and increased resting pool of SVs as assessed by imaging of SV release in cultured neurons. CDK5/calcineurin and cAMP/PKA presynaptic signalling are dysregulated, resulting in an aberrant phosphorylation of their downstream effectors synapsin1 and SNAP25, well‐known regulators of SV release competence. An acute pharmacological restoration of physiological CDK5 and cAMP/PKA activity fully normalises the SV pools in neurons lacking bassoon. Finally, we demonstrate that CDK5‐dependent regulation of PDE4 activity interacts with cAMP/PKA signalling and thereby controls SV release competence. These data reveal that bassoon organises SV pools in glutamatergic synapses via regulation of presynaptic phosphorylation and cAMP homeostasis and indicate a role of CDK5/PDE4/cAMP axis in the control of neurotransmitter release.

Neuroligin‐2 controls the establishment of fast GABAergic transmission in adult‐born granule cells

“…Bssn is an active‐zone protein involved in vesicular release that is essential for the formation of central synapses (Davydova et al, 2014; Gundelfinger et al, 2015; Montenegro‐Venegas et al, 2022). To get a closer insight into the functional state of perisomatic synaptogenesis, we counted active zones per soma (Bssn+ puncta) colocalizing with PV‐Tom terminals in GCs expressing SCR or shNL2 (Figure 4a,b).…”

EGCG attenuates METH self‐administration and reinstatement of METH seeking in mice

“…The results showed that EGCG/AA NPs significantly increased the amplitude of evoked IPSCs in both METH group (151 ± 5.2% of baseline, p < 0.001) and saline group (148 ± 6.4% of baseline, p < 0.001), and there was no significant difference between the two groups in the magnitude of EGCG/AA NP‐induced potentiation of IPSCs ( p = 0.617; Figure 4A,B). EGCG has been proved to increase intracellular cAMP, 18 which facilitates neurotransmitter release through the activation of protein kinase A (PKA) at many synapses, both excitatory and inhibitory 19,20 . After treatment with PKA inhibitor H89 in METH and saline groups, we found that H89 prevented the effect of EGCG/AA NPs on IPSCs in METH ( p < 0.001) and saline ( p < 0.001) groups (Figure 4A,B).…”

“…EGCG has been proved to increase intracellular cAMP, 18 which facilitates neurotransmitter release through the activation of protein kinase A (PKA) at many synapses, both excitatory and inhibitory. 19,20 After treatment with PKA inhibitor H89 in METH and saline groups, we found that H89 prevented the effect of EGCG/AA NPs on IPSCs in METH ( p < 0.001) and saline ( p < 0.001) groups (Figure 4A,B). Taken together, EGCG/AA NPs treatments prevented the METH SA-induced reduction of GABAergic inhibition.…”

Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression

“…It is transiently unquenched upon contact with neutral pH of the extracellular solution, and is quenched again upon endocytosis and vesicular re-acidification, thereby allowing fast real-time assessment of SV recycling at individual synapses. We utilized an established field stimulation protocol [ 59 , 61 ] of 40 AP at 20 Hz to mobilize fusion of docked SVs corresponding to the readily releasable pool (RRP), followed by a train of 900 AP at 20 Hz in order to release SVs of the so-called recycling pool (RP). RRP and RP comprises of all release-competent SVs and signify the total recycling pool (TRP).…”

“…Sample size for all experiments was set according to previous publications, where the comparable parameters were assessed using the same methodology [ 52 , 61 ]. Statistical analyses were performed using Graphpad Prism 9 (GraphPad Software, San Diego, California, USA).…”