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

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

[1]  P. Sengupta.  The Laboratory Rat: Relating Its Age With Human's , 2013, International journal of preventive medicine.

[2]  Yun Wang,et al.  A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex. , 2015, Cell reports.

[3]  Masahiko Watanabe,et al.  Release probability of hippocampal glutamatergic terminals scales with the size of the active zone , 2012, Nature Neuroscience.

[4]  C. Jahr,et al.  Multivesicular Release at Climbing Fiber-Purkinje Cell Synapses , 2001, Neuron.

[5]  O. Sporns,et al.  Mapping the Structural Core of Human Cerebral Cortex , 2008, PLoS biology.

[6]  B. Katz,et al.  Quantal components of the end‐plate potential , 1954, The Journal of physiology.

[7]  R. Silver,et al.  High-Probability Uniquantal Transmission at Excitatory Synapses in Barrel Cortex , 2003, Science.

[8]  I. Soltesz,et al.  Distinct Endocannabinoid Control of GABA Release at Perisomatic and Dendritic Synapses in the Hippocampus , 2010, The Journal of Neuroscience.

[9]  Rafael Yuste,et al.  Of Mice and Men, and Chandeliers , 2008, PLoS biology.

[10]  H. V. Gersdorff,et al.  The ubiquitous nature of multivesicular release , 2015, Trends in Neurosciences.

[11]  Csaba Varga,et al.  HUMAN AND , 2022 .

[12]  C. D. de Kock,et al.  Mechanisms Underlying the Rules for Associative Plasticity at Adult Human Neocortical Synapses , 2013, The Journal of Neuroscience.

[13]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[14]  J R Kremer,et al.  Computer visualization of three-dimensional image data using IMOD. , 1996, Journal of structural biology.

[15]  J. Clements,et al.  Unveiling synaptic plasticity: a new graphical and analytical approach , 2000, Trends in Neurosciences.

[16]  P. Somogyi,et al.  Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations , 2008, Science.

[17]  E. Neher,et al.  Separation of Presynaptic and Postsynaptic Contributions to Depression by Covariance Analysis of Successive EPSCs at the Calyx of Held Synapse , 2002, The Journal of Neuroscience.

[18]  R. Angus Silver,et al.  Estimation of nonuniform quantal parameters with multiple-probability fluctuation analysis: theory, application and limitations , 2003, Journal of Neuroscience Methods.

[19]  D. O. Hebb,et al.  The organization of behavior , 1988 .

[20]  E. Neher,et al.  Estimation of quantal parameters at the calyx of Held synapse , 2002, Neuroscience Research.

[21]  E. Capaldi,et al.  The organization of behavior. , 1992, Journal of applied behavior analysis.

[22]  Márton Rózsa,et al.  Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex , 2012, The Journal of Neuroscience.

[23]  A. Marty,et al.  Vesicular Release Statistics and Unitary Postsynaptic Current at Single GABAergic Synapses , 2015, Neuron.

[24]  Robert K. S. Wong,et al.  Human epileptic neurons studied in vitro , 1981, Brain Research.

[25]  Guy Eyal,et al.  Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex , 2015, Cerebral cortex.

[26]  T. Südhof,et al.  The Morphological and Molecular Nature of Synaptic Vesicle Priming at Presynaptic Active Zones , 2014, Neuron.

[27]  Javier DeFelipe,et al.  Double bouquet cell in the human cerebral cortex and a comparison with other mammals , 2005, The Journal of comparative neurology.

[28]  N. Tamamaki,et al.  Hippocampal pyramidal cells excite inhibitory neurons through a single release site , 1993, Nature.

[29]  Z. Nusser,et al.  Quantal Size Is Independent of the Release Probability at Hippocampal Excitatory Synapses , 2005, The Journal of Neuroscience.

[30]  G. Tamás,et al.  Excitatory Effect of GABAergic Axo-Axonic Cells in Cortical Microcircuits , 2006, Science.

[31]  R. Silver,et al.  Estimation of quantal parameters with multiple-probability fluctuation analysis. , 2007, Methods in molecular biology.

[32]  Paul Greengard,et al.  Three-Dimensional Architecture of Presynaptic Terminal Cytomatrix , 2007, The Journal of Neuroscience.

[33]  G. Buzsáki.  Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning , 2015, Hippocampus.

[34]  W. Singer.  Development and plasticity of cortical processing architectures. , 1995, Science.

[35]  Csaba Varga,et al.  Complex Events Initiated by Individual Spikes in the Human Cerebral Cortex , 2008, PLoS biology.

[36]  E. Neher,et al.  What is Rate-Limiting during Sustained Synaptic Activity: Vesicle Supply or the Availability of Release Sites , 2010, Front. Syn. Neurosci..

[37]  Karl J. Friston,et al.  Structural and Functional Brain Networks: From Connections to Cognition , 2013, Science.

[38]  P A Schwartzkroin,et al.  Intracellular study of human epileptic cortex: in vitro maintenance of epileptiform activity? , 1984, Science.

[39]  T. Ishikawa,et al.  A Single Packet of Transmitter Does Not Saturate Postsynaptic Glutamate Receptors , 2002, Neuron.

[40]  László G Puskás,et al.  GABAergic Neurogliaform Cells Represent Local Sources of Insulin in the Cerebral Cortex , 2014, The Journal of Neuroscience.

[41]  T. Freund,et al.  Endocannabinoid-Mediated Long-Term Depression of Afferent Excitatory Synapses in Hippocampal Pyramidal Cells and GABAergic Interneurons , 2012, The Journal of Neuroscience.

[42]  R. Silver,et al.  Locus of frequency‐dependent depression identified with multiple‐probability fluctuation analysis at rat climbing fibre‐Purkinje cell synapses , 1998, The Journal of physiology.

[43]  Z. Nusser,et al.  Release Probability-Dependent Scaling of the Postsynaptic Responses at Single Hippocampal GABAergic Synapses , 2006, The Journal of Neuroscience.

[44]  H Korn,et al.  Transmission at a central inhibitory synapse. II. Quantal description of release, with a physical correlate for binomial n. , 1982, Journal of neurophysiology.