Introduction
A special lecture in the on demand content of the 2025 Virtual Component of SfN2025 is a lecture by Prof. Vanderhaeghen. This lecture is called: Mechanisms Linking Human Neuron Development, Evolution and (Dys)function. Prof. Pierre P. Vanderhaeghen is a physician and professor at the VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
During the recent development of our human ancestors, the cerebral cortex—the part of the brain responsible for thinking and social skills—changed quickly. Prof. Vanderhagens talk explores how these brain circuits evolved. He looks at special genes that are unique to humans and some specific characteristics of our brain cells, like how they use energy. Understanding how these human-specific factors affect the growth and function of brain cells can help us learn more about our evolutionary history and reveal surprising connections to between developmental timing and human brain function and diseases.
This article is resource linked to the material on Unit 4: Brain Development and Unit 5: Cognition of this website.
Human synaptic neoteny may be required for experience dependent cortical circuit development and plasticity
Neuronal development in the human cerebral cortex is considerably prolonged compared to that of other mammals. It results in extended critical periods of learning and plasticity that have been proposed to play a role in the acquisition of human-specific cognitive features.
Global and Gene-specific mechanisms controlling the temporal scale of human cortical development
Gene-specific mechanisms
Prof. Vanderhaeghen first addressed the gene specific mechanisms controling the temporal scale of human cortical development. This is described in the article: Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition
Libé-Philippot, Baptiste et al (2024). There is also a recent presentation by prof. Vanderhaeghen on YouTube: Journée François Jacob : The Living Clock: Biology in the Flow of Time(4)
Human-specific genes SRGAP2B/C are required for human cortical neuron neoteny.
SRGAP2B/C slow down synaptogenesis by increasing the synaptic levels of SYNGAP1. A tug of war between synaptic SRGAP2A and SYNGAP1 sets the tempo of synaptogenesis. SRGAP2B/C act as genetic modifiers of the function of SYNGAP1
Global – Metabolic mechanisms of species specific developmental tempo
In the paragraph before this one we talked about species- specific genes in the GRN (Gene Regulaty Network).
The figure above is from the article: Metabolic mechanisms of species-specific developmental tempo Iwata, Ryohei et al. (2024), B and C are these regulatory and species specific genes that we talked about. In addition to these proceeses there are also global processes “outside”of the developmental GRN have an impact on timing without alteration of GRN components (D in the figure).
Researchers have established a causal link between mitochondria and metabolism and crucial aspects of neural development, from neurogenesis to neuronal maturation and plasticity. Thus connecting mitochondrial metabolism to the timing of neuronal development.
Disrupted neonoteny
The prolonged neotenic development of cortical neurons and circuits characterizes human brain ontogeny. Researchers consider neoteny essential for acquiring advanced cognitive functions. Cognitive functions are often affected in individuals with intellectual disabilities (ID) and autism spectrum disorders (ASDs)
In this article: SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo
Vermaercke, Ben et al. (2024) the authors use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency. SYNGAP1 haploinsufficiency one of the most prevalent genetic causes of ID/ASDs.
They discover that human neurons lacking SYNGAP1 develop and mature their connections much faster than normal. Consequently this also leads to problems with how flexible those connections are. To research the link between neoteny and neuronal plasticity they looked at ocular dominance plasticity using the classical model of Hubel and Torsten (see presentation at YouTube at 27:12, work in progress, not published yet). At the circuit level, neurons lacking SYNGAP1 respond to visual stimulation much earlier than expected, by several months.
These findings indicate that human neuronal neoteny require SYNGAP1 at the cellular level. Thus these findings esteblish novel connections between human-specific developmental mechanisms and intellectual disabilities (ID) and autism disorders (ADs).. Thereby presenting a framework linking developmental timing and human brain function and diseases.