Molecular Psychiatry (2011) 16, 478–490 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp FEATURE REVIEW The role of neurotrophic factors in autism T Nickl-Jockschat and TM Michel Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany Autism spectrum disorders (ASDs) are pervasive developmental disorders that frequently involve a triad of deficits in social skills, communication and language. For the underlying neurobiology of these symptoms, disturbances in neuronal development and synaptic plasticity have been discussed. The physiological development, regulation and survival of specific neuronal populations shaping neuronal plasticity require the so-called ‘neurotrophic factors’ (NTFs). These regulate cellular proliferation, migration, differentiation and integrity, which are also affected in ASD. Therefore, NTFs have gained increasing attention in ASD research. This review provides an overview and explores the key role of NTFs in the aetiology of ASD. We have also included evidence derived from neurochemical investigations, gene association studies and animal models. By focussing on the role of NTFs in ASD, we intend to further elucidate the puzzling aetiology of these conditions. Molecular Psychiatry (2011) 16, 478–490; doi:10.1038/mp.2010.103; published online 12 October 2010 Keywords: autism; autism spectrum disorders; BDNF; genes; neurotrophic factors; NT-3 Introduction Although the aetiology of ASD is still not fully understood, twin and adoption studies suggest a Approximately one child per 145 babies born in the strong genetic role in the manifestation of the United States will be diagnosed with some form of disorder.8–11 Monozygotic twins show concordance autism spectrum disorder (ASD) throughout their rates of approximately 70–90%, whereas they are only 1 lifespan according to new estimates. The differences 0–10% in dizygotic twins.12,13 However, in addition noted in individuals with autism relate to develop- to genetic risk factors, there is evidence for an associa- ment deficiencies of language, social interaction tion with a variety of other conditions, including skills, repetitive and stereotyped movements and prenatal exposure to noxae such as alcohol, behaviours, hyperactivity, sensory disturbances, thalidomide or sodium-valproate as well as obstetric 2,3 restricted interests and more rarely self-injury. complications, pre- and post-natal brain damage, Additional challenging aspects of ASD are comorbid chromosomal aberrations such as fragile X-syndrome, 4 disorders, such as epilepsy, gastrointestinal pro- tuberous sclerosis and 22q11.2 deletion syndrome 5 6 blems and sleep disorder. The clinical presentation among others.14–16 of autism is complex and variable, and therefore the One of the most consistent findings in autism is an term ASD is often used in this context. According to increased brain size during development.17–20 Chil- the ICD-10 (International Statistical Classification of dren with autism seem to undergo an abnormally Diseases and Related Health Problems, Tenth Revi- accelerated brain growth during development.18,19,21–23 sion), ASD is described as a pervasive developmental It has been suggested that the formation of neuronal disorder. Differentiation from other developmental connections or the elimination of inappropriate disorders such as Rett syndrome, which show over- connections does not proceed in the typical manner. lapping symptoms and a similar neurobiology to Striking neuropathological findings, such as fewer ASD, is not always easy, especially in the very early Purkinje cells, smaller neuronal size and decreased stages. Rett syndrome is a comparatively rare disorder dendritic branches in subjects diagnosed with ASD, with clinical proximity to ASD, but in contrast to have been reported for various brain regions, such as ASD, a mono-genetic background can be defined in a the cerebellum,24–28 the hippocampus and the amyg- 7 majority of cases. Rett syndrome, which affects dale.25,26 Magnetic resonance imaging studies have girls only, is characterized by a profound learning also shown grey and white matter changes such as disability following early normal development, with a reduced neuronal and axodendendritic pruning in consistent cluster of clinical features. autism.29–34 Lately, inflammatory processes have also been discussed in the aetiopathology of autism.28 A Correspondence: Dr TM Michel, Department of Psychiatry and vast body of research has been undertaken in the last Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, decade to elucidate the underlying pathophysiology Aachen, D-52074, Germany. E-mail: [email protected] of autism. Received 13 January 2010; revised 31 August 2010; accepted 6 The development and maintenance of the central September 2010; published online 12 October 2010 nervous system is influenced by several different Neurotrophic factors in autism T Nickl-Jockschat and TM Michel 479 mechanisms, one of the most prominent being low affinity,59–62 but can be regulated by receptor neurotrophic factors (NTFs).35–41 dimerization, structural modifications or association NTFs do not only have a key role in processes such with the p75 receptor.63,64 as brain development and maintenance of neurons Substrate binding leads to Trk dimerization and, and their dentrites throughout life, but they also therefore, to trans-autophosphorylation at two tyrosine critically influence the formation and elimination of residues (Tyr490 and Tyr785) in the cytoplasmatic neuronal connections. They have been discussed in domain of the receptor, activating the intracellular many studies as promising candidates responsible for signalling cascade.62 A key molecule interacting with part of the alterations seen in autism.35–43 these phosphotyrosine motifs is the Src homologous NTFs comprise a range of different protein super- and collagen-like (Shc) adaptor protein. Shc links families. At least six factors belong to the neurotro- Trk signalling to two major signalling pathways: the phin family: nerve growth factor (NGF), brain-derived Ras/Raf/ERK and the phosphatidylinositol-3 kinase growth factor (BDNF), neurotrophin (NT)-3, NT-4, (PI3K) pathway. NT-5 and NT-6.44–47 The neurotrophins are a family of After activation, Shc interacts with Grb2. Regarding closely related proteins that were first identified as the Ras/Raf/ERK pathway, Grb2 then binds to SOS survival factors for sympathetic and sensory neu- (son of sevenless). The Shc/Grb2/SOS complex rons.48 The core functions of neurotrophins during attaches itself to the membrane through the inter- neurodevelopment include regulation of cell prolif- action of Shc with the phosphorylated receptor, eration, migration and survival. They also modulate and mediates signalling to the Ras/mitogen-activated axonal and dendritic outgrowth, synapse formation protein kinase pathway.65,66 The neurotrophins’ and other neuroplastic processes.49 ability to activate Raf depends on Rap1, a small Further neurotrophic superfamilies include neuro- endosomal G-protein.67 The active Ras/Raf/ERK path- kines such as ciliary NTF (CNTF) and leukaemia way influences, for example, transcription of the inhibitory factor (LIF), insulin-like growth factors cyclic AMP-response element (CREB) transcription (for example, IGF-1 and IGF-2), as well as the vast factor. Overall, this pathway has effects on the cell transforming growth factor-b (TGF-b) superfamily (for cycle, neurite outgrowth and synaptic plasticity.68 example, TGF-b1, -b2 and -b3), and their distant Alternatively, Shc-bound Grb2 can activate PI3K relative glial cell line-derived neurotrophic factor through the Gab1 (Grb2-associated binder-1). PI3K (GDNF). Additionally, there are a variety of other can propagate cellular survival through Akt (protein proteins that can at least partly exert an influence on kinase B) activities,65 and also mitogenic signalling, neurotrophic functions, although they are not con- cell survival, cytoskeletal remodelling and vesicular sidered as NTFs themselves. trafficking.69 Furthermore, individual NTFs and their receptors Binding of phospholipase-Cg to activate Trk con- are quite distinct and are subject to considerable stitutes an additional, Shc-independent pathway, changes in the course of neural development.50,51 resulting in the release of inositol phosphates and The proteins of the neurotrophin family have a activation of protein kinase C.65,70 molecular weight of 13 kDa (NGF) to 27 kDa (BDNF, Through a different set of adaptor proteins, p75 NT-3) and high isoelectric points (9–10.5). BDNF is signalling results in increases in Jun N-terminal one of the most abundant NTFs in mammalian brains. kinase, nuclear factor-kB and ceramide.71 P75 is The neurotrophin genes, like other peptide growth capable of mediating apoptosis in a pathophysio- factors, encode a precursor peptide.52,53 Thus, the logical context, for example, after seizure or inflam- protein forms of neurotrophins exist in the human mation72,73 and—in oligodendrocytes—after spinal brain, both in the mature and in its precursor form injury,74 and also physiologically during neurodeve- (for example, proBDNF). The precursor form is lopment.75 secreted in both a basal and an activity-dependent Surprisingly, pro-neurotrophins display higher fashion and is processed extracellularly to its mature affinities for the p7556 and are more effective form by proteolytic cleavage.54–56 inductors of p75-dependent apoptosis.56,74 Thus, Only one frequent, nonconservative