Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

Abstract

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

“…Evaluation of neurobehavioral development in rodents represents an essential study paradigm to model neurodevelopmental disorders such as Down syndrome and autism spectrum disorders (ASDs) which are characterized by mental retardation and delays in growth and development787980. In rodents like mice and rats, the early postnatal period is associated with a burst of brain growth, synaptogenesis, myelination, and development of motor and sensory modalities7879.…”

“…80. Examination was started on PND1 and was carried out until PND21 (or until the appearance of developmental milestone/neurological reflex) daily between 12:00–15:00 hours in a set up made specifically for the purpose in the Behavior Lab of the Department of Neurochemistry at NYSIBR.…”

“…The following primary antibodies were used: mouse monoclonal anti-synaptophysin (1:3000, Millipore, Temecula, CA, USA), rabbit monoclonal anti-PSD95 (1:1000, Cell Signaling Technology, Danvers, MA, USA), rabbit polyclonal anti-BDNF, N-20 (1:500, Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit polyclonal anti-CNTF, FL-200 (1:500, Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit polyclonal anti-TrkB (total) (1∶500; Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit polyclonal anti-CREB (1:1000, Cell Signaling Technology, Danvers, MA, USA), rabbit polyclonal anti-phosphorylated CREB, Ser133 (1:1000, Cell Signaling Technology, Danvers, MA, USA), rabbit monoclonal anti GSK3β (1:1000, Cell Signaling, Danvers, MA, USA), rabbit polyclonal anti-phosphorylated GSK3β, Ser9 (1:1000, Cell Signaling, Danvers, MA, USA), rabbit polyclonal anti-protein kinase A catalytic subunit alpha (PKAcα) (1:1000, Santa Cruz Biotechnology, Santa Cruz, CA, USA), mouse monoclonal anti-STAT3 (1:1000; Cell Signaling Technology, Danvers, MA, USA), rabbit monoclonal anti-pSTAT3, Tyr705 (1:1000; Cell Signaling Technology, Danvers, MA, USA), and rabbit polyclonal antibody to GAPDH (1:1000, Santa Cruz Biotechnology, Santa Cruz, CA, USA) as loading control. The blots were developed and quantified as described before6780. For quantification of different protein levels, each immunoreactive band was normalized to its corresponding GAPDH band.…”

Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample

“…3a and b), which encodes the cytoskeletal-associated proteins that constitute a link between the membrane and the cytoskeleton involved in the signal transduction pathways. Evidence from functional studies suggest that JAK2 is involved in the JAK-STAT cascade, a process that includes the development, maintenance, and survival of central nervous system glial cells and neurons as well as enhanced brain-derived neurotrophic factor expression (Kaur et al 2005;Kazim et al 2015). Previous studies have demonstrated that JAK-STAT activation signals play a crucial role in ASD immune dysfunction (Ahmad et al 2017), and it was found to participate in the MAPK cascade process (https://www.ncbi.nlm.nih.gov/gene/ 3717) in the MAPK signaling pathway.…”

7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders

“…The sera from autistic children also caused significant reductions in the mRNA and protein expression of BDNF in the cerebral cortex of these rats, possibly through increasing oxidative stress by increased amounts of reactive oxygen species and lipid peroxidation present in the sera (Chauhan et al, 2004). Interestingly, a small ciliary neurotrophic factor (CNTF) mimetic, P6, given at the same time as the sera injection, was able to reverse both behavioural and molecular deficits (Kazim et al, 2015). CNTF is thought to assert neuroprotection at least partly via elevating BDNF levels by enhancing its transcription (Bolognin et al, 2012).…”