Brain region-specific decrease in the activity and expression of protein kinase A in the frontal cortex of regressive autism

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.

Figure 1. PKA activity in different brain regions from regressive autism, non-regressive autism, and age-matched control subjects.

The autism group comprises combined regressive and non-regressive autism sub-groups. Brain homogenates were prepared, and activity of PKA was measured as described in Materials and Methods. Data represent mean ± S.E.

Figure 2. Relative protein levels of PKA (C-α) in the frontal cortex of regressive autism, non-regressive autism, and age-matched control subjects.

Western blot analyses of C-α subunit of PKA in the frontal cortex of individuals with regressive and non-regressive autism, and age-matched control subjects are represented in Fig. 2A. The relative density of PKA (C-α) normalized with the density of β-actin (loading control) is shown in Fig. 2B. Data represent mean ± S.E.