Postnatal development and maturation of layer 1 in the lateral prefrontal cortex and its disruption in autism

Abstract

Autism is a neurodevelopmental connectivity disorder characterized by cortical network disorganization and imbalance in excitation/inhibition. However, little is known about the development of autism pathology and the disruption of laminar-specific excitatory and inhibitory cortical circuits. To begin to address these issues, we examined layer 1 of the lateral prefrontal cortex (LPFC), an area with prolonged development and maturation that is affected in autism. We focused on layer 1 because it contains a distinctive, diverse population of interneurons and glia, receives input from feedback and neuromodulatory pathways, and plays a critical role in the development, maturation, and function of the cortex. We used unbiased quantitative methods at high resolution to study the morphology, neurochemistry, distribution, and density of neurons and myelinated axons in post-mortem brain tissue from children and adults with and without autism. We cross-validated our findings through comparisons with neighboring anterior cingulate cortices and optimally-fixed non-human primate tissue. In neurotypical controls we found an increase in the density of myelinated axons from childhood to adulthood. Neuron density overall declined with age, paralleled by decreased density of inhibitory interneurons labeled by calretinin (CR), calbindin (CB), and parvalbumin (PV). Importantly, we found PV neurons in layer 1 of typically developing children, previously detected only perinatally. In autism there was disorganization of cortical networks within layer 1: children with autism had increased variability in the trajectories and thickness of myelinated axons in layer 1, while adults with autism had a reduction in the relative proportion of thin axons. Neurotypical postnatal changes in layer 1 of LPFC likely underlie refinement of cortical activity during maturation of cortical networks involved in cognition. Our findings suggest that disruption of the maturation of feedback pathways, rather than interneurons in layer 1, has a key role in the development of imbalance between excitation and inhibition in autism.

Imbalance of Laminar-specific Excitatory and Inhibitory Circuits of the Orbito frontal Cortex in Autism

“…Each sample yielded a large number of data points, because we typically examine a large volume fraction of the areas sampled, and thus increase the number of individual axons and neurons examined. The high sampling fraction used in our studies minimized the variability within each analyzed case, and further increased statistical power, as we have described [34][35][36][37][38]. Our previous work [5,27,[35][36][37] and power analysis showed that the sampling ratios exceed the samples needed to detect differences with a greater than 90% probability, and large effect population size (0.8) with ≤ 10% error, as recommended [39].…”

“…The high sampling fraction used in our studies minimized the variability within each analyzed case, and further increased statistical power, as we have described [34][35][36][37][38]. Our previous work [5,27,[35][36][37] and power analysis showed that the sampling ratios exceed the samples needed to detect differences with a greater than 90% probability, and large effect population size (0.8) with ≤ 10% error, as recommended [39]. We further minimized variability, using only the OFC from right hemispheres of adults (mean age of Control group ± SD: 49.8 ± 15.2; mean age of ASD group ± SD: 36 ± 7.1) with similar PMI (mean PMI of Control group ± SD: 24.2 ± 6.7; mean PMI of ASD group ± SD: 25 ± 8.3).…”

“…Histochemistry and immunostaining were performed as previously described [35,37]. Brie y, we stained sections with Nissl to visualize the overall neuronal population in OFC.…”

Inhibition of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Activity Reverses Behavioral Deficits in a Rodent Model of Autism

“…Previous studies show disrupted synaptic development in pre-frontal cortex after VPA treatment in rodents [34,35]. We therefore determined total STEP61 levels in pre-frontal cortex after pre-natal VPAexposure in mice at one-month age by immunoblot analysis.…”

Dissecting Autism Genetic Risk Using Single-cell RNA-seq Data

“…Previous studies have investigated autism risk by cortex laminar architecture. However, studies based on co-expression analysis [15,16] or neurochemical experiments [49,50] reported conflicting conclusions, that either deep or superficial layers of cortex are associated with autism. These early studies were based on a small number of high-confidence autism risk genes.…”