BioLinks Journal Club 6: Synaptic connectivity and Human Evolution

Paper:” ​A human-specific modifier of cortical circuit connectivity and function improves behavioral performance”

Please read the short introduction to this week’s research paper below, which includes a background over crucial information involved. Don’t worry if you don’t understand everything in this intro - we will break it down over the course of the week and dive into the techniques and exact experiments included in the paper . Please remember questions that come up from reading this or anything of particular interest you would like to discuss more on Monday!

Why do human brains have such advanced processing capabilities? Scientists have discovered a human specific development gene SRGAP2C that is responsible for increased brain connectivity and response to stimuli in the cortex, an outer region of the brain responsible for processing many of the central nervous system’s signals.. But how did a human specific copy of this gene arise? During meiosis, the cell division process that creates our eggs and sperm (gametes) our parents’ chromosomes will recombine in a way that accounts for the variation between offspring and their parents. This involves crossing over, a process where part of the maternal and paternal corresponding chromosome will switch with each other, resulting in offspring with a unique combination of a mother and father’s gene copies. During this process, genes can be duplicated and incorporated into the egg or sperms gametes, and eventually, the offspring. Over generations of this phenomenon, several Human Specific Gene Duplications ( HSGDs) have come about as one factor differentiating humans from other organisms with common ancestors. For the SRGAP2 gene, humans have branched off from the ancestral copy of the gene, SRGAP2A, when the SRGAP2A gene was duplicated into the human specific SRGAP2C.

Brain connectivity refers to the way in which the neurons in our nervous system interact with each other. Neurons form networks as they pass stimulus-triggered impulses from the sending terminal of one neuron (axon) to the receiving end of another. Synapses are the gaps between two neurons, and structural and chemical elements that allow a signal to cross a synapse are what allow these connected pathways to form. When you smell food and your mouth salivates, one single neuron isn’t responsible for responding to the scent and eliciting a response. It's like dominoes, where synapses allow the key contact between one piece and the next that allows the chain to keep falling. Synaptic components and activity are responsible for the complex connectivity in the human brain - which is why we have such high cognitive ability.

So SRGAP2C’s role as this critical cortical development modifier was tested in mice by measuring synaptic activity. But mouse neurons regularly express SRGAP2A, so their neurons had to be engineered to express SRGAP2C and nullify SRGAP2A function, effectively humanizing them for this gene. The mouse cells began to display more synapse formations, and

human-like development of those synapses, suggesting that SRGAP2C was very key to the way human cortical connectivity has developed to allow the movement, sensation and personality we observe in ourselves! But how exactly does expression of the SRGAP2C gene cause enhanced connectivity and cognitive output? This paper investigates just that, by looking internally at how synaptic changes in mice with SRGAP2C (instead of the natural SRGAP2A) lead to connectivity changes, and seeing if this pattern remains externally by seeing whether the mice also exhibit visible behavioral changes when mutated.