Duration in the maturation process of the human brain is exaggerated when compared with other mammals and especially among primates, and thus the ability for learning is advanced.
Failure to achieve this may account for some of the neurodevelopmental disorders more prevalent today.
However, a research endeavor led by Prof. Pierre Vanderhaeghen (VIB-KU Leuven) in conjunction with scientists from Columbia University and Ecole Normale Supérieure has recently reported findings that correlate two human DNA-specific genes to a known one SYNGAP1 which is associated with cognitive impairment disorders such as autism.
While their Umısı catami study reconstructs various shaping processes of strategic communication, in the present paper the authors make a surprisingly straightforward connection between evolution of the human brain and various neurodevelopmental disorders.
To other mammals, however, the brain of a human being is one that exhibits the longest. In particular within the human cerebrum’s cortex region where most if not all of the higher cognitive functions originate, routines referred to as synapses take quite some time to develop that is years as compared to months in other animals such as macaques or mice.
This prolonged stage of development known as neoteny is regarded as the basis of the remarkable cognitive and learning capabilities of an individual. On the other hand, brain neoteny has also been hypothesized as a causal factor for many neurodevelopmental disabilities including impairments of intellectual functioning and autism spectrum disorders.
The lab of Pierre Vanderhaeghen at the VIB-KU Leuven Center for Brain & Disease Research previously showed that the extended period of development of the human cerebral cortex is largely accounted for by human-specific molecular circuitry in neurons.
Then, they want to comprehend how these molecular timers function across human neurons. In their latest study, the research team investigated the contributions of two specific genes, SRGAP2B and SRGAP2C, which are present only in humans.
These genes were identified by Cécile Charrier in the laboratory of Prof. Franck Polleux at Columbia University, USA, and are known to function in the mouse cortical neuronal synapse overproduction where their expression is excessive. Whether these genes behave similarly in human neurons, however, has not been investigated.
To tackle this problem, Dr. Baptiste Libé-Philippot, Postdoc at Vanderhaeghen’s group, inhibited SRGA2B and SRGAP2C genes in human neurons that were subsequently implanted into mouse brain and synapse formation was followed for 18 months.
As Dr. Libé-Philippot explains: RNAi knockdown of these genes in human neurons led to a striking increase in the rate of synaptic development. By 18 months, the synapses are similar to those of typically developing children aged between five and 10 years.
This is akin to what is seen in the enhanced synapse formation seen in some types of autism. The team then investigated the underlying genetic mechanisms behind the pronounced effects of SRGAP2B and SRGAP2C on human neuron neoteny.
They narrow down their investigation to the SYNGAP1 disease gene that has been implicated in intellectual disability and autism spectrum disorder.
Interestingly, they also found that the augmentation of the SRGAP2 and SYNGAP1 proteins regulates the speed of synapse maturation in humans.
Even more interestingly, the effects of both SRGAP2B and SRGAP2C are those of upregulation of the SYNGAP1 gene as well as restoration of some of the neuronal phenotypes associated with the absence of SYNGAP1.
This finding bolsters our knowledge of the human-specific molecules and the corresponding pathways of neurodevelopmental diseases and why these disorders are more common in humans.
Prof. Pierre Vanderhaeghen looks ahead with optimism. This investigation clarifies the principles governing the long process of maturation of synapses in human.
It is amazing to find out that the same genes that are involved in the evolution of the human brain also have the potential to modify the expression of specific brain diseases.
This could have important clinical relevance: more research is needed to understand how human-specific mechanisms of brain development affect learning and other behaviors and how their dysregulation can lead to brain disorders.
It becomes conceivable that some human-specific gene products could become innovative drug targets.
Reference: Human cortical neuron neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition at the synapse., Neuron (2024).
