Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

Schmidt, Ewoud R.E.; Polleux, Franck

doi:10.3389/fncir.2021.787164

Cited by 25 publications

(16 citation statements)

References 146 publications

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“…For this study, we focused on cortical subregion L2-3, recording from neurons down to 1200 μm laminar depth from the pia. Studying L2-3 of the human brain is of particular interest since these layers expanded disproportionally during human evolution 24 . Up to ten neurons were recorded simultaneously in whole-cell configuration, allowing us to functionally characterize these cells and to probe for synaptic connections between them (Figure 1A-C).…”

Section: Human Multineuron Patch-clamp Recordings With Large Data Sam...mentioning

confidence: 99%

Cellular and Synaptic Diversity of Layer 2-3 Pyramidal Neurons in Human Individuals

Planert

Mittermaier

Grosser

et al. 2021

Preprint

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Computation within cortical microcircuits is determined by functional properties of the neurons and their synaptic interactions. While heterogeneity of inhibitory interneurons is well established, the anatomical, physiological, and molecular differentiation of excitatory pyramidal neurons is not fully resolved. To identify functional subtypes within the pyramidal neuron population, we focused on human layer 2-3 cortex which greatly expanded during evolution. We performed multi-neuron patch-clamp recordings in brain slices from the temporal cortex of 22 epilepsy patients. We characterized the electrophysiological properties of up to 80 pyramidal neurons per patient, enabling us to assess inter- and intra-individual functional variability. Hierarchical clustering of the high-dimensional parameter space yielded functionally distinct clusters of pyramidal neurons which were present across individuals. This may represent a generic organizational principle converging with previously described transcriptomic heterogeneity. We further observed substantial heterogeneity in physiological parameters with intra-individual variability being severalfold larger than inter-individual variability. The phenotypic variability within and across pyramidal neuron subtypes has important implications for the computational capacity of the cortical microcircuit.

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Section: Human Multineuron Patch-clamp Recordings With Large Data Sam...mentioning

confidence: 99%

Cellular and Synaptic Diversity of Layer 2-3 Pyramidal Neurons in Human Individuals

Planert

Mittermaier

Grosser

et al. 2021

Preprint

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“…Given its importance for information processing, the development of the synapse provides an avenue for the understanding of the unrivaled cognitive abilities of humans. It has been observed that accompanied by the increase in the size of the human brain, the spine density is higher in human cortical neurons compared to other primates or rodents ( Defelipe, 2011 ; Schmidt and Polleux, 2021 ). The most prominent feature of synaptogenesis in humans is the protracted developmental window ( Liu et al, 2012 ).…”

Section: Evolutionary Perspectives On Molecular Mechanisms Of Synapto...mentioning

confidence: 99%

“…Thus, by manipulating neural activities, we can examine the molecular events that impact the destinies of synapses. Last but not least, synaptogenesis, though largely conserved, has been constantly reshaped during evolution ( Schmidt and Polleux, 2021 ), which endows humans with unprecedented cognitive capabilities and provides avenues to develop treatments and therapies for neurological disorders and diseases.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of synaptogenesis

Cai

Luo

Feng

et al. 2022

Front. Synaptic Neurosci.

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Synapses are the basic units for information processing and storage in the nervous system. It is only when the synaptic connection is established, that it becomes meaningful to discuss the structure and function of a circuit. In humans, our unparalleled cognitive abilities are correlated with an increase in the number of synapses. Additionally, genes involved in synaptogenesis are also frequently associated with neurological or psychiatric disorders, suggesting a relationship between synaptogenesis and brain physiology and pathology. Thus, understanding the molecular mechanisms of synaptogenesis is the key to the mystery of circuit assembly and neural computation. Furthermore, it would provide therapeutic insights for the treatment of neurological and psychiatric disorders. Multiple molecular events must be precisely coordinated to generate a synapse. To understand the molecular mechanisms underlying synaptogenesis, we need to know the molecular components of synapses, how these molecular components are held together, and how the molecular networks are refined in response to neural activity to generate new synapses. Thanks to the intensive investigations in this field, our understanding of the process of synaptogenesis has progressed significantly. Here, we will review the molecular mechanisms of synaptogenesis by going over the studies on the identification of molecular components in synapses and their functions in synaptogenesis, how cell adhesion molecules connect these synaptic molecules together, and how neural activity mobilizes these molecules to generate new synapses. Finally, we will summarize the human-specific regulatory mechanisms in synaptogenesis and results from human genetics studies on synaptogenesis and brain disorders.

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“…In addition, density, composition, and maturation rates of synapses differ between species, potentially contributing to the evolutionary variation of neurotransmission properties, cognitive ability, and behavioral repertoire (14)(15)(16)(17)(18)(19)(20). For example, prolonged maturation or neoteny of human synapses has been suggested as a possible explanation for the emergence of human-specific cognitive traits (21)(22)(23). But we still know little about the underlying molecular mechanisms.…”

Section: Main Textmentioning

confidence: 99%

A cross-species proteomic map reveals neoteny of human synapse development

Wang

Pang

Zhou

et al. 2022

Preprint

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The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here, we generated a cross-species proteomic map of synapse development in the human, macaque, and mouse neocortex. By tracking the changes of >1,000 postsynaptic density (PSD) proteins from midgestation to adolescence, we found that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that the human PSD matures about three times slower than other species and contains higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of the RhoGEF signaling in human neurons delays the morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Together, our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

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Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

Cited by 25 publications

References 146 publications

Cellular and Synaptic Diversity of Layer 2-3 Pyramidal Neurons in Human Individuals

Cellular and Synaptic Diversity of Layer 2-3 Pyramidal Neurons in Human Individuals

Molecular mechanisms of synaptogenesis

A cross-species proteomic map reveals neoteny of human synapse development

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