Relationship Between Decreased Activity of Protein Kinase C and Behavioral Abnormalities in Regressive Autism

Background: Autism is a neurodevelopmental disorder with unknown etiology.  In some cases, typically developing children regress into clinical symptoms of autism, a condition known as regressive autism. The cause of regression in autism is not understood.  Protein kinases are known to play important roles in cellular signaling pathways, and are involved in neurodevelopment, neuronal functions, gene expression, memory, and cell differentiation. The brain synapses are the building blocks of memory formation, and synaptic strength contributes to learning and memory. 

Objectives: Recently, we reported decreased activity of protein kinase A (PKA) in the frontal cortex of subjects with regressive autism.  In this study, we analyzed the activity of protein kinase C (PKC) in the cerebellum and different regions of cerebral cortex from subjects with regressive autism, autistic subjects without clinical history of regression, and age-matched control subjects.

Methods: The postmortem frozen brain regions, i.e., cerebellum, and cortices from frontal, temporal, parietal and occipital regions of brains from autism and control subjects were obtained from NICHD Brain and Tissue bank for Developmental Disorders at the University of Maryland.  The tissues were homogenized (10% w/v) in cold buffer containing 50 mM Tris-HCl (pH 7.4), 8.5% sucrose, 2 mM EDTA, 10 mM b-mercaptoethanol and protease inhibitor cocktail in a Downs homogenizer with 5 strokes at 4 ⁰C. The protein concentration was assayed by the Bradford method. Activity of PKC was measured by enzyme linked-immunosorbent assay kits. 

Results: In the frontal cortex of subjects with regressive autism, PKC activity was significantly decreased by 57.1% as compared to age-matched control subjects (p = 0.0085), and by 65.8% as compared to non-regressed autistic subjects (p = 0.0048).  PKC activity was unaffected in the temporal, parietal and occipital cortices, and in the cerebellum in both autism groups, i.e., regressive and non-regressed autism as compared to control subjects.  These results suggest brain region-specific alteration of PKC activity in the frontal cortex of subjects with regressive autism.  Analysis of correlation between PKC activity and behavior parameters of subjects with autism showed a negative correlation between PKC activity and restrictive, repetitive and stereotyped pattern of behavior (r= -0.084, p = 0.0363) in autistic individuals, suggesting involvement of PKC in behavioral abnormalities in autism. 

Conclusions: These findings suggest that regression in autism may be attributed, in part, to alterations in G-protein-coupled receptor-mediated signal transduction involving PKA and PKC in the frontal cortex.