Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

Abstract

Although autism is highly genetic, "idiopathic" cases, for which there is no known genetic basis, may be due to epigenetic or environmental factors. Indeed, recent efforts have been highly successful in identifying hundreds of genes, as well as interacting epigenetic and environmental factors that contribute to autism susceptibility, corroborating the importance of gene x environment interactions in the etiology of autism. Nevertheless, a more thorough understanding of the proteins and pathways that lead from genes to behavior is desperately needed.Genetic studies have implicated molecules involved in synapse development and plasticity in autism pathogenesis. Among these are brain-derived neurotrophic factor (BDNF), its receptor, tropomyosin-related kinase B (TrkB), and their signaling pathways including mammalian target of rapamycin (mTOR), which is increased in most forms of syndromic autism. Notably, abnormalities in these molecules have also been found in idiopathic autism. Postmortem brain tissue of subjects with idiopathic autism exhibits imbalances in BDNF isoforms, reduced TrkB and downstream effectors PI3 kinase (PI3K), mTOR, Epidermal growth factor receptor pathway substrate 8 (Eps8) and the excitatory synaptic marker postsynaptic density protein 95 kDa (PSD-95). Furthermore, similar TrkB pathway deficits including reduced TrkB/mTOR signaling and PSD-95, along with autistic-like behavior, have been found in valproic acid-exposed rodents, a model of environmental/epigenetic causes of autism. Our studies in both human idiopathic autism and the valproic acid-induced rodent model suggest that decreased signaling through the mTOR pathway can be as damaging as its over-activation. AutismAutism is a lifelong neurodevelopmental disorder characterized by disturbances in social interactions and communication and stereotyped, repetitive patterns of interests, activities and behaviors [1,2]. It is one of a heterogeneous group of disorders called Autism Spectrum Disorders (ASD) that share these characteristics but differ in course, symptom pattern or level of functioning. ASD is perhaps the most common and handicapping neurological disorder of childhood in terms of prevalence, morbidity, outcome and cost to society. ASD represents a significant public health problem and poses a huge burden for education and social service systems. Recent estimates of the prevalence of ASD in the US and Canada (CDC, NEDSAC) were 1 in 68 [3,4]. There is currently no diagnostic test or cure available for autism, and its etiology is unknown.Epidemiological and twin studies point to a major role for genetic factors in ASD [5,6], with a complex pattern of transmission thought to be the result of perhaps as many as 1000 interacting genes [7-9]. Hundreds of rare genetic events that carry increased risk for ASD, many of them arising de novo [10][11][12][13][14], have been identified [15][16][17][18][19][20][21].However, genetic changes account for only half of all autistic cases; environmental influences are responsible for the rema...

Neuroimmunologic and Neurotrophic Interactions in Autism Spectrum Disorders: Relationship to Neuroinflammation

“…2 ). The increase in pro-BDNF in idiopathic ASD creates an imbalance between neurotrophic/growth (BDNF/TrkB) and apoptotic/pruning (pro-BDNF/p75 NTR ) (Fahnestock and Nicolini 2015 ). The altered levels of BDNF isoforms in individuals with ASD might prove to be an integral part of its pathology.…”

“…Whereas TrkB-FL signals neurotrophic activity through Ras-MAPK, PLC-γ and PI3 K pathways (Kaplan and Miller 2000 ), the truncated isoforms sequester BDNF, inhibit TrkB-FL signaling and regulate neurite outgrowth via Rho GTPase signaling (Fenner 2012 ; Wong and Garner 2012 ). Thus, changes in TrkB isoform balance also lead to alterations in downstream signaling, including the PI3 kinase-dependent pathways Akt-mTOR and Eps8-Rac which govern spine protein synthesis and stability (Fahnestock and Nicolini 2015 ). This hypothesis is supported by decreased Akt and mTOR total protein and phosphorylation in the cortex of autistic patients (Nicolini et al 2015 ; Sheikh et al 2010 ) and mutations affecting Akt-mTOR signaling (TSC1/2, PTEN and MeCP2) which cause disorders with high rates of autism (Kelleher and Bear 2008 ).…”

Effect of non‐invasive brain stimulation on behavior and serum brain‐derived neurotrophic factor and insulin‐like growth factor‐1 levels in autistic patients

“…Neurotrophic factors, mainly insulin‐like growth factor 1 (IGF‐1) and brain‐derived neurotrophic factor (BDNF), have been implicated in ASD. Examination of humans and animal models has revealed alterations of neurotrophic factor levels and their associated signaling pathways that might contribute to the disease (Fahnestock & Nicolini, 2015; Ohja et al, 2018; Riikonen, 2017). The members of the insulin‐like growth factors 1 and 2 (IGF‐1 and IGF‐2, respectively) gene family are critical trophic modulators in the central nervous system (CNS).…”

“…Reduced BDNF receptor, TrkB, is also seen in postmortem brain tissue of subjects with autism (Nicolini et al, 2015). BDNF/TrkB, like IGF‐1/IGF‐1 receptor, activates MAPK and PI3K‐AKT1 pathways that affect synaptic protein expression and brain network connectivity (Costales & Kolevzon, 2016; Fahnestock & Nicolini, 2015; Nicolini et al, 2015).…”

The Presynaptic Scaffold Protein Bassoon in Forebrain Excitatory Neurons Mediates Hippocampal Circuit Maturation: Potential Involvement of TrkB Signalling

“…Of note, the neurotrophic factor BDNF is highly abundant in glutamatergic hippocampal synapses [ 21 ] and its signalling through TrkB plays a fundamental role in hippocampal neurogenesis, circuit maturation and synapse elimination in distinct brain regions [ 22 , 23 , 24 , 25 ]. Furthermore, altered BDNF/TrkB signalling has been observed in both rodent models [ 26 , 27 ] and patients suffering from autism spectrum disorders and schizophrenia [ 28 , 29 , 30 , 31 ]. Intriguingly, hippocampal BDNF levels of Bsn ΔEx4/5 mice are profoundly elevated in adulthood (~12 weeks-old) while only a moderate/insignificant increase in BDNF was detected during adolescence (~4 weeks-old) [ 32 , 33 ].…”