A possible link between decreased protein kinase A (PKA) levels in the frontal cortex and the loss of developmental skills at 15-24 months was recently reported in PLoS.ONE by Abha Chauhan and colleagues at the NYS Institute for Basic Research and Developmental Disabilities in Staten Island, New York.
PKA, which is critical for learning and memory, has been implicated in other neuropsychiatric disorders including bipolar affective, obsessive compulsive, and panic disorder as well as schizophrenia, but this is the first study to investigate its role in autism.
Pinpointing cerebral PKA levels
Deficient PKA levels were detected in the frontal cortex of postmortem tissue samples from individuals who had suffered from regressive autism. In contrast, PKA levels in the temporal, parietal, and occipital cortices and cerebellum were normal, according to these scientists, who therefore consider the finding, “brain-region-specific” in regressive autism. PKA levels in samples from age-matched individuals with non-regressive autism and control subjects were similar across all brain regions, they add. Notably, PKA activity in the frontal cortex of people with regressive autism was significantly decreased compared to levels from other autistics or developmentally normal controls.
PKA plays a major role in neuronal development
As a cyclic adenosine monophosphate (cAMP)-dependent protein kinase, PKA is important for the growth, plasticity, and regeneration of neurons. If the frontal cortex is involved in regressive autism, as this study suggests, then abnormalities in PKA could affect signal transduction which, in turn, might influence the behavior of neurons such as TrkB, and engrailed-2, which are thought to be involved in the development of autism, explains Chauhan. Thus, she notes,
“the regression seen in this subgroup may be associated, at least in part, with the decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.”
Study suggests possible therapeutic interventions
If the findings of this investigation prove correct, therapies known to increase PKA activity, such as cAMP analogs and rolipram, might prove useful for therapeutic intervention in patients with regressive autism. However, “a study using a larger number of brain samples is needed to confirm the present findings as well as to explore the impact of various comorbidities and their medications on the results,” says Chauhan.
Note: Postmortem frozen samples were obtained from the National Institute of Child Health and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders at the University of Maryland in Baltimore. There were between 7 and 10 samples from autistic individuals and 9 and 10 from age-matched, typically developed control subjects; the numbers depending on different brain regions (cerebellum and cortices from the frontal, temporal, parietal and occipital lobes). The autistic group was further divided into two subgroups: regressive and non-aggressive; regressive autism was defined as “normal early development followed by a loss of previously acquired skills.”
Source: Abha Chauhan, PhD
Ji L, Chauhan V, Flory MJ, et al. Brain region-specific decrease in the activity and expression of protein kinase a in the frontal cortex of regressive autism. PLoS ONE 6, 1-8 (2011) Pub med:
More about autism and autism research at the Simons Foundation Autism Research Initiative.
More about the structure of protein kinase A at Advanced Light Source.
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