Chandellier Cells Modify the Balance of Excitation/Inhibition in Autism

Background: An interneuron alteration has been proposed as a source for the modified balance of excitation/inhibition in the cerebral cortex in autism. We previously demonstrated a decreased number of parvalbumin (PV)-expressing interneurons in prefrontal cortex in autism. Our most recent data indicates that a specific type of PV-expressing neuron is altered in autism, the Chandellier (Ch) cell. Chandellier cells are interneurons that generate fast-spiking action potentials and synchronize the activity of numerous pyramidal cells through rhythmic inhibition. Chandellier cells innervate the axon initial segment of pyramidal cells – in contrast to the rest of interneuron input that takes place on dendrites. As a consequence, the loss of small numbers of Ch cells could critically alter pyramidal neuron output and impair cerebral cortex function.

Objectives: As discussed in our previous publication investigating PV+ interneurons in the autistic neocortex (Hashemi et al., 2016), the decreased number of PV+ Ch cells we detected in in autism may represent an actual decrease in cell number, on the other hand it may represent an apparent decrease in cell number resulting from reduced PV protein levels in Ch cells. To determine if the number of Ch cells, rather that the expression of PV by Ch cells, is altered in autism, we quantified Ch cartridges in autism and control tissue. If the number of Ch cells is decreased we also expect to find a decrease in the number of Ch cartridges.

Methods: We collected prefrontal BA9, BA46, and BA47 in samples obtained from 10 autism, 10 autism with seizure, and 10 control age-matched cases. The tissue was obtained from the Autism Tissue Program (ATP), currently known as Autism BrainNet, and the UC Davis Medical Center. We cut the tissue and performed immunostaining for GAT1 that clearly labels cartridges. We quantified the number of cartridges in 3 mm wide sections of cortex, and statistically compared data between groups.

Results: Our preliminary data indicate that in area BA 46 there is a decrease in the number of GAT1-cartriges in the autism and the autism with seizure groups when compare to the control group.

Conclusions: Here we demonstrated that both Ch cells and also their terminal axons, the Ch cartridges, are numerically decreased in autism. A decrease in the number of Ch cells could result from different factors including 1) decreased production of Ch cells by precursor cells during prenatal development, 2) increased cell death among Ch cells during development, or 3) altered migration of Ch cells to their final destination in the cerebral cortex. This finding expand our understanding of GABAergic system functioning in the human cerebral cortex in autism, which will impact translational research directed towards providing better treatment paradigms for individuals with autism.