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

Date Published: August 31, 2011

Publisher: Public Library of Science

Author(s): Lina Ji, Ved Chauhan, Michael J. Flory, Abha Chauhan, Krystof Bankiewicz.

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.

Partial Text: 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. While the causes of ASDs remain elusive, ASDs are considered to be heterogeneous and multifactorial disorders that are influenced by both genetic and environmental factors. The onset of autism is gradual in many children. However, 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]. The reported incidence of regressive autism varies in different studies from 15% to 62% of cases [4]–[7]. In a few cases, regression may significantly affect language, with lesser impact in other domains such as social interaction or imaginative play [4], [8]. On the other hand, some children may regress especially in social functions and not in language [9].

ASDs are complex neurodevelopmental disorders. The complexity of ASDs is further increased because some affected individuals fall in the sub-group of regressive autism [7]. Behavioral changes in regressive autism fall into two broad domains: (a) loss of vocalization and (b) loss of social skills. The rate of regressive autism varies from 15% to 62% of cases in different studies [4]–[7]. While Lord et al. reported that 29% of the children they studied who were diagnosed with autism had lost language skills for meaningful words, and another 9% lost non-word vocalizations [5], Goldberg et al. reported regression in 62% of children [4]. Loss of spoken words generally associates with loss of social behavior [6], but some affected children show only loss of social skills [4]. We report here that individuals with regressive autism have decreased PKA activity in the frontal cortex of the brain. This decreased PKA activity in autistic regression may be attributed to the decreased protein contents of PKA because the protein content of PKA (C-α subunit) was also decreased in the frontal cortex of individuals with regressive autism. Interestingly, such changes were not observed in other brain regions of individuals with regressive autism, or in the frontal cortex and other brain regions of individuals with non-regressive autism. These results suggest that alterations in PKA activity and PKA expression are specific to the frontal lobe in regressive autism.