Human pyramidal to interneuron synapses are mediated by multi-vesicular release and multiple docked vesicles

Abstract

Classic theories link cognitive abilities to synaptic properties and human-specific biophysical features of synapses might contribute to the unparalleled performance of the human cerebral cortex. Paired recordings and multiple probability fluctuation analysis revealed similar quantal sizes, but 4-times more functional release sites in human pyramidal cell to fast-spiking interneuron connections compared to rats. These connections were mediated on average by three synaptic contacts in both species. Each presynaptic active zone (AZ) contains 6.2 release sites in human, but only 1.6 in rats. Electron microscopy (EM) and EM tomography showed that an AZ harbors 4 docked vesicles in human, but only a single one in rats. Consequently, a Katz’s functional release site occupies ~0.012 μm2 in the human presynaptic AZ and ~0.025 μm2 in the rat. Our results reveal a robust difference in the biophysical properties of a well-defined synaptic connection of the cortical microcircuit of human and rodents.DOI: http://dx.doi.org/10.7554/eLife.18167.001

Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex

“…These strong connections specifically from PCs to inhibitory interneurons have since been reported in the frontal, prefrontal, parietal, and temporal cortices, where the VLEs often are suprathreshold, driving assemblies of inhibitory interneurons to fire after a single PC spike [11,37]. Similar strong connections between two individual neocortical neurons have not been found in nonhuman species [37–39].…”

“…The hypothesis on strong glutamate release is supported by our finding that the small EPSP connections were unable to generate LTD by single fiber activity, but they showed the mGluR-dependent plasticity when multiple fibers were activated simultaneously with local extracellular stimulation [55]. Indeed, a recent study revealed that human neocortical PC–FSIN synapses with VLEs have more transmitter vesicle release sites, although the glutamate release quantal size is similar compared to synapses in rat neocortex [37]. This indicates multivesicular release in synapses with VLEs, and it is interesting to speculate that the conversion to common small EPSPs via the presynaptic LTD might reflect their transformation from a multivesicular release site to a single vesicle-releasing synapse.…”

“…These strong connections specifically from PCs to inhibitory interneurons have since been reported in the frontal, prefrontal, parietal, and temporal cortices, where the VLEs often are suprathreshold, driving assemblies of inhibitory interneurons to fire after a single PC spike [11,37]. Similar strong connections between two individual neocortical neurons have not been found in nonhuman species [37–39]. Analyses of large datasets from rodent visual and somatosensory cortices have revealed that neurons in local networks are not randomly connected, but specific local connectivity patterns exist between neuron types, and the strongest excitatory synapses control local network activity [40–42].…”

“…A common form of mGluR-dependent LTD characterized in the extracellular stimulation experiments of glutamatergic synapses in the rodent cortex [24] converts the VLEs to small amplitude EPSPs. This LTD suppresses VLE synapses through a presynaptic mechanism most likely controlling the vesicular transmitter release as indicated by the changes in the EPSP amplitude PPR and the coefficient of variation in the depressed synapses [37]. The LTD of VLEs in FSINs, many of which are also pv+, involves the group I mGluRs.…”

“…However, compared to recordings with 2 mM extracellular calcium, this modification is unlikely to strongly affect the high-frequency firing-evoked synaptic release and the long-term plasticity in FSIN synapses: the probability of synaptic release in VLEs in FSINs is already very high at 2 mM Ca 2+ , and only slightly modulated by further increase of calcium [37]. Yet, as demonstrated in the recent study by Molnar et al [37], the VLE release probability can markedly decrease when extracellular calcium is reduced from 3 mM to 1.5 mM, which is considered lower range of the cerebrospinal fluid total calcium level in physiological conditions [51]. Therefore, it is also possible that in calcium concentrations close to 1.5 mM, the PC firing pattern used in this study may not be sufficient for such a robust LTD as reported here in the FSINs.…”