Blood from children with autism induces autistic features in rats

Autism and autism spectrum disorders (ASD), which present evidences suggests to result from multiple causes, has been shown to be consistently associated with accelerated brain growth during early development followed by impaired brain growth and development. In a fascinating study just published in PLOS One the investigators report the ability to induce anatomical and behavioral features of autism in their laboratory subjects by injecting serum from children with autism. They were also able to ameliorate these effects by treating with Peptide 6 (P6), an agent that mimics a natural neuroprotective peptide. The authors note:

"Neurotrophic factors play essential roles in all stages of central nervous system development and maintenance; they critically influence the formation and elimination of neuronal connections. Several studies suggest that aberrant cerebral connectivity and synaptic plasticity constitute essential features of the pathogenesis of autism. Thus, neurotrophic factors which are essential mediators of neuronal and synaptic plasticity have been hypothesized to play a major role in the pathophysiology of autism."

Abnormal neurotrophic factors in patients with autism

Neurotrophic factors such as BDNF (brain derived neurotrophic factor) and CNTF (ciliary neurotrophic factor) are altered in autism patients:

"Altered brain, CSF, and serum levels of neurotrophic factors have been reported in patients with autism. For example, serum level of BDNF, which plays an essential role in brain development, neurogenesis and synaptogenesis, and synaptic plasticity, was shown to be decreased in children, adolescents, and adults with autism...The serum levels of CNTF were found to be lower and the levels of FGF-2 and LIF were found to be higher in children with autism compared to age-matched healthy controls. Previously, increased oxidative stress which is widely implicated in the pathophysiology of autism was shown to block CNTF activity in neurons which is essential for neuronal survival and maintenance...Our data suggest that the levels of various neurotrophic factors are altered in sera from children with autism and this imbalance along with the increased oxidative stress could be among the primary factors responsible for the altered development and neurodegeneration observed in both in vivo and in vitro models."

 Neuronal oxidative stress increased by sera from children with autism

Oxidative stress which can damage DNA and promote immune dysfunction has been associated with the altered brain development seen in autism.

"We found that culturing the mouse primary cortical neurons in the presence of sera from autistic children result in increase in levels of ROS and lipid peroxidation. Similarly, in- creased oxidative stress-induced DNA damage was observed in brain tissue from rats exposed to sera from autistic children during the early period of development. These findings support the notion that altered brain environment contributes to increased oxidative stress in early developmental stages in autism. Increased oxidative stress has been suggested to lead to membrane lipid abnormalities, mitochondrial dysfunction, excitotoxicity, and immune dysfunction in autism, and may ultimately contribute to the behavioral phenotype of autism."

Inflammation increased

Neuroinflammation is emerging as a common denominator in a wide range of neuro-developmental and neuropsychiatric disorders. Here the authors showed that sera from children with autism increased the inflammatory activity of brain immune cells (astrocytes and glia).

"Inflammatory changes especially astroglial activation have been described in the brains of patients with autism and may contribute to the pathogenic mechanisms involved in cortical and neuronal dysfunction. Astrocytes and microglia play critical roles in the neurobiological processes of cortical organization, neuroaxonal guidance, and synaptic plasticity. Increased GFAP [glial fibrillary acidic protein, a marker for neuroinflammatory astrocyte activity] level observed in the present study in autism sera treated rats could signify gliosis, reactive injury and impaired neuronal migration processes."

Moreover...

"The rescue of astorgliosis by P6 treatment in the present study signifies the potential therapeutic usage of neurotrophic factor based strategy for ameliorating neuroinflammation in ASD."

Amelioration of autistic features by P6 treatment

Remarkably, the authors were able to significantly reduce the damage done with the peptide P6 which appears to mediate its beneficial effects through BDNF:

"The beneficial effect we observed with P6 treatment further strengthens the idea that autism could be caused by an early imbalance of neurotrophic factors and increased oxidative stress...In the current study, we found that P6 was able to rescue autism serum-induced neurodegeneration and oxidative stress in cultured neurons and rat brains. The neuroprotective effect of P6 could have been because of increased BDNF expression we observed in P6 treated rat brains. We previously showed that P6 and its fragment peptide, Peptide 021 (P021) enhance BDNF mRNA and protein levels; BDNF is known to exert protective effect against oxidative stress. Recently, a relationship has been suggested between BDNF, sonic hedgehog (SHH), and oxidative stress in autism. Wu et al showed that BDNF induces up-regulation of SHH at both mRNA and protein levels, and the protective effect of BDNF in cortical neurons could be abolished by using SHH signaling inhibitor. Based on this, we can speculate that the protective effect of P6 against autism serum-induced neurodegenration and oxidative stress could have been mediated via BDNF."

Summary

This extraordinary study expands our understanding of the causative factors in autism and suggests advances in treatment by modulating pathways of oxidative stress, inflammation and neurodegeneration. The authors conclude:

"One of the most remarkable findings of the current study is the development of several features of autism in young rats whose brains were exposed to sera from autistic children via i.c.v. injections. This single finding strongly suggests the important role brain environment plays during early development in the pathophysiology of autism. Early postnatal exposure of brain tissue to sera from autistic children which had abnormalities in neurotrophic factor levels led to developmental delay and social communication, interaction, and memory deficits in young rats. Several of these deficits such as developmental delay and social memory deficits were rescued by P6 treatment. Interestingly, the early postnatal exposure to autistic sera resulted in increased oxidative stress induced DNA damage and neurodegeneration in cortical tissue of young rats providing the structural correlate for behavioral abnormalities observed in these rats. Remarkably, P6 treatment was able to rescue these structural abnormalities probably via increased BDNF expression."

Therapeutic potential

"...this study provides evidence regarding the neurotrophic abnormalities in autism and the potential role they play in the pathophysiology of the disease. We speculate that the brain milieu of autistic children is altered and favors increased oxidative stress and neurodegeneration. Ameliorating the neurotrophic imbalance during early stages of brain development can serve as a potential therapeutic approach for autism. P6 represents a new class of neurotrophic peptide mimetics that has potential therapeutic value for ASD and related conditions."

This, of course, further validates testing for and targeting factors contributing to neuroinflammation and oxidative stress on an individual case basis. Moreover, it heightens awareness of practitioners to the need to assess the inflammatory and oxidative status of pregnant patients, and even better prior to pregnancy.