Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism

Lina Ji,Abha Chauhan,Michael J Flory,Ved Chauhan,Krystof Bankiewicz

doi:10.1371/journal.pone.0023751

Abstract

Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP–dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.

Highlights

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impairment in social interactions and verbal/non-verbal communication skills, and restricted, repetitive and stereotyped patterns of behavior [1]
When all autism cases were compared with the age-matched control group, no significant difference was found in protein kinase A (PKA) activity in any of these brain regions, PKA activity in the frontal cortex was found to be reduced by 34.7% in the autism vs. control group
When the autism group was divided into two sub-groups, depending on whether there was a clinical history of regression or not, unadjusted two-tailed t-test showed a significant decrease in PKA activity in the frontal cortex of individuals with regressive autism as compared to the developmentally normal control group (p = 0.0278) and the non-regressive autism group

Summary

Introduction

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impairment in social interactions and verbal/non-verbal communication skills, and restricted, repetitive and stereotyped patterns of behavior [1]. According to a recent report from the Centers for Disease Control and Prevention, the prevalence of ASDs is 1 in 110 for children 8 years of age [2]. The symptoms of ASDs are typically present before the age of 3 years, and are often accompanied by abnormalities in cognitive functioning, learning, attention, and sensory processing. In regressive autism, children first show signs of normal social and language development but lose these developmental skills at 15–24 months and develop autistic behavior [3]. Regression may significantly affect language, with lesser impact in other domains such as social interaction or imaginative play [4,8]. Some children may regress especially in social functions and not in language [9]

Methods

Results

Conclusion