In my thesis entitled “The see-through brain: Changes in inhibition through space and time in a mouse model for Kleefstra Syndrome” I investigate the development of inhibitory neurons in a mouse model of Kleefstra Syndrome, a syndromic form of intellectual disability with strong autistic traits (Ehmt1+/- mouse).
We first investigated the impact of Ehmt1 haploinsufficiency on the maturation of Parvalbumin-positive GABAergic neurons during the critical periods for the auditory, somatosensory and visual cortices. We found that while PV+ neuron maturation was generally delayed in Ehmt1+/- mice, it eventually reached wild-type levels—except in layer 4 of the primary somatosensory cortex.
We then scaled up from single brain areas to the entire mouse brain. To this end we implemented whole-brain clearing and imaging using the iDISCO technique and developed a new data analysis pipeline, FriendlyClearmap. We validated this new pipeline by imaging the three largest groups of GABAergic interneurons in wild type mice: PV+, SST+, and VIP+.
When we used this pipeline on Ehmt1+/- mice, we discovered changes in all three main GABAergic cell classes, with VIP+ neurons being more abundant in the Ehmt1+/- cortex and SST+ neurons being less abundant in the Ehmt1+/- cortex and the amygdala. Most notably, we identified an early hypermaturation of PV+ neurons in the amygdala, which persisted into adulthood and leads to increased inhibitory transmission at the circuit level.
To conclude, with this thesis I show that Ehmt1+/- haploinsufficiency affects the entire inhibitory system of the mouse brain, but in a region- and cell-type specific way – we found both delays as well as speedups, overabundance as well as scarcity, depending on the time and place.