Shared and divergent principles of synaptic transmission between cortical excitatory neurons in rodent and human brain

Abstract

Information transfer between principal neurons in neocortex occurs through (glutamatergic) synaptic transmission. In this focussed review, we provide a detailed overview on the strength of synaptic neurotransmission between pairs of excitatory neurons in human and laboratory animals with a specific focus on data obtained using patch clamp electrophysiology. We reach two major conclusions: (1) the synaptic strength, measured as unitary excitatory postsynaptic potential (or uEPSP), is remarkably consistent across species, cortical regions, layers and/or cell-types (median 0.5 mV, interquartile range 0.4–1.0 mV) with most variability associated with the cell-type specific connection studied (min 0.1–max 1.4 mV), (2) synaptic function cannot be generalized across human and rodent, which we exemplify by discussing the differences in anatomical and functional properties of pyramidal-to-pyramidal connections within human and rodent cortical layers 2 and 3. With only a handful of studies available on synaptic transmission in human, it is obvious that much remains unknown to date. Uncovering the shared and divergent principles of synaptic transmission across species however, will almost certainly be a pivotal step toward understanding human cognitive ability and brain function in health and disease.

Variation and convergence in the morpho-functional properties of the mammalian neocortex

“…Despite potential differences in the capacity to form synaptic connexions, given the higher density of spines on human neurons (Benavides-Piccione et al, 2002 ), the rate of local functional connectivity (around 12% in mice, 14% in rats, and 14% in humans) and the number of synapses per connexion (between ~2 and 4) are reported to be comparable between rodents and humans. This similarity extends to the median amplitude (~0.5 mV despite substantial differences between studies and cortical regions, see de Kock and Feldmeyer, 2023 for review), latency, and kinetics of unitary (evoked by the firing of single presynaptic neurons) EPSPs reaching the soma, which show remarkable consistency across a variety of species (human and mouse: Testa-Silva et al, 2014 ; Szegedi et al, 2016 ; Seeman et al, 2018 ; Campagnola et al, 2022 ; Hunt et al, 2023 ; mouse: Oswald and Reyes, 2008 ; Lefort et al, 2009 ; Ko et al, 2013 ; Jouhanneau et al, 2015 ; Luo et al, 2017 ; rat: Mason et al, 1991 ; Hardingham and Larkman, 1998 ; Holmgren et al, 2003 ; Yoshimura et al, 2005 ; Feldmeyer et al, 2006 ; Hardingham et al, 2010 ; macaque and rat: Povysheva et al, 2006 ; cat and rat: Thomson et al, 2002 ). It also predicted that a similarly small number of simultaneously active L2/3-L2/3 synapses (between ~125 and 145) is required to generate a somatic AP in human and rat cell models (Eyal et al, 2018 ).…”

“…The number of synaptic vesicles in the putative readily releasable pool of L5 neurons is similar in both species, but the resting pool is at least 2-fold larger in humans, which could facilitate rapid refilling of the releasable pool during sustained high-frequency activity (human: Yakoubi et al, 2019 ; rat: Rollenhagen et al, 2015 , 2018 ). Finally, it is suggested that the mean amplitude of the unitary EPSP at the L5 pyramidal-to-pyramidal connexion (including ET and IT neurons) is comparable between species (~0.6 mV), but further human studies are needed to confirm these results (rodent: de Kock and Feldmeyer, 2023 for review; see also Lefort et al, 2009 ; Hardingham et al, 2010 ; Kerr et al, 2013 ; human: Seeman et al, 2018 ).…”

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition

“…The evolutionary origin of these adaptations remains elusive, given that genes encoding proteins involved in synaptic transmission and energy metabolism did not undergo significant evolutionary changes in the human lineage [14]. Consistent with this view are electrophysiologic data obtained in human and rodent brains showing that the fundamental unit of synaptic transmission is remarkably conserved in mammals [15]. Instead, evolutionary changes have occurred in the regulatory elements of genes expressed in the human brain [2,4,16,17], with more than 80% of adaptive sequence evolution in humans thought to be regulatory [8].…”