عوامل گلوتامات در اختلالات طیف اوتیسم: روند کنونی

Glutamate transmission dysfunction has been found in various preclinical models of Autism Spectrum Disorders (ASD), thus the glutamate system is a target for therapeutics. This report reviews current treatments for glutamate dysfunction in ASD models and clinical trials. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5) have been tested in preclinical models of autism. Black and Tan Bachyuric (BTBR) mice model behavioral phenotypes of the three core diagnostic domains of autism, e.g. social deficits, impaired language and communication, and repetitive behaviors. A significant reduction in repetitive self-grooming was observed after mGluR5 antagonist administration in BTBR mice. SHANK 3 deficient mice which have altered synaptic transmission and plasticity, were administered IGF-1 treatment to reverse these deficits based on the hypothesis that reduced AMPA receptor levels reflect less mature synapses. Clinical trials have been carried out in ASD with glutamate NMDA receptors, but current findings are not sufficient for conclusions on safety and efficacy. Memantine is an NMDA antagonist under investigation in controlled trials that hopefully will provide new insight on its use in autism. Studies using novel treatments with other glutamatergic agents are also underway and encouraging results have been observed with N-acetylcysteine in treating irritability in ASD.

Autistic spectrum disorders (ASD) are characterized by three core behavioral domains: social deficits, impaired language and communication, and repetitive behaviors (APA, 2000). A wide clinical heterogeneity, ranging from severe social and communication impairments to mild personality traits, awaits further definition in more precise clinical subgroups and phenotypes. Autistic disorder, childhood disintegrative disorder, pervasive development disorder not otherwise specified (PDD-NOS, or ‘atypical autism’), and Asperger syndrome are all considered to be ASD. Current estimates of the prevalence of autistic disorder are around 20/10,000 and the prevalence for PDD not otherwise specified is around 30/10,000, according to current surveys. Recent studies examining the whole spectrum of PDDs have consistently provided estimates in the 60–70/10,000 range, making PDD one of the most frequent childhood neurodevelopmental disorders. The rise in the incidence of ASD during the past two decades is surprising and not fully understood. It might be explained by the use of broader diagnostic criteria, increased attention of the medical community and/or awareness, but a number of other factors, including environmental determinants, are under investigation (Fombonne, 2009). Glutamate, the main excitatory neurotransmitter in the brain, has a leading role during development since it modulates neuronal formation and synaptic strengthening in the early phases and due to its primary role in neuronal plasticity and cognitive functioning (Lodge, 2009). Glutamate receptors are diffused throughout the brain and are widely represented in the cerebellum and hippocampus, regions implicated in ASD pathogenesis. Glutamate signaling abnormalities are involved in the complex development of Autism Spectrum Disorders (ASD) as reported in several models, but many aspects are still unresolved. The pathways of abnormal glutamate transmission and the mechanisms leading to the specific clinical characteristics are still poorly understood (Carlson, 2012 and Choudhury et al., 2012). In particular, their role in influencing social and communication abnormalities, restricted interests and repetitive behaviors, the three core domains of ASD, is still not clear. The term autism will be used throughout the text as the abbreviation of ASD.

Glutamate signaling abnormalities have been found to be involved in the complex interaction between synaptic maturation and plasticity that have been reported to be abnormal in ASD. Many aspects are still unclear, as to the mechanisms involved at the cellular and receptor levels, due to the great complexity of the glutamatergic system. Animal models are providing a host of new information on the genes and receptors implicated in altered social function and repetitive behaviors. Glutamate transmission dysfunction has different pathways of altered excitatory transmission, through a downregulation of AMPA receptors, abnormalities of NMDA receptor mediated plasticity and altered mGluR signal transduction, all involved in the core abnormalities of ASD and associated with cognitive deficits. In spite of the increasing amount of data on genetic abnormalities, further research is needed on the genetic underpinnings and on the relationships between the core domains of ASD and glutamate signaling. Abnormality in glutamate excitatory transmission appears to be related to repetitive behaviors and interests, as well as to susceptibility for seizures and anxiety as associated disorders. There is less evidence for the impact of glutamate signaling on the core social domains of autism in current preclinical models. ASD models indicate that glutamate excitatory transmission is often disrupted in a complex framework that likely interferes with a network necessary for normal synaptic function. Glutamatergic abnormalities within these networks may contribute to characterizing behavioral subgroups and phenotypes in ASD. The differences that exist among these models should be clarified in upcoming research. For example, FMR1 knockout mice demonstrated social deficits that are not mediated by mGluR5, suggesting alternative non-glutamatergic mechanisms underlying social deficits in fragile-X. However, neuroligin expression appeared to be involved in social deficits, as well as in mGlu5 dysfunction, in the FMR1 knock out model, further complicating the issue (Dahlhaus & El-Husseini, 2010). Thus, genetic influences on social components vary between models and further research is necessary to clarify these issues. Glutamatergic NMDA antagonists, amantadine, memantine, and dextromethorphan, as well as agonists such as d-cycloserine, have been employed in clinical trials to counteract behavioral disturbances and to attenuate the core symptoms of ASD, thus far yielding only inconsistent findings. Memantine has had the most attention but additional research with adequate study design is still needed. The literature on memantine is mostly limited to underpowered research based on varying methods of investigation, often insufficient for drawing clear conclusions or for making comparisons. The add-on studies using memantine with risperidone were preliminary and the reported favorable outcome on irritability should be replicated. Overall, controlled trials with memantine must be available before we can draw any kind of firm conclusions and additional data should soon be available, as a number of clinical trials are underway. For the other glutamatergic agents, there are sparse and very limited findings that preclude any kind of consideration as yet. 5.1. Future directions Safer and more effective therapeutics are still needed to target both behavioral and core ASD symptoms, and alternative options to the current limited set of choices would be welcome. The possibility of using glutamatergic agents to reduce repetitive behaviors in children with autism is important and strong efforts are needed to obtain a clearer picture. mGluR antagonists are under intense investigation in human trials, predominantly in FXS, associated or not with ASD. Negative modulators of mGluR5 have been developed for the treatment of FXS, but no clinical trials have been conducted in idiopathic autism and this should be a field of future investigation. Additional ASD models are need for testing and replication to determine whether glutamate dysfunction mediates specific behaviors, as this appears to be true but has not been fully demonstrated. The glycine receptor is a possible target since it is an adjuvant at the NMDA receptor and it could potentially decrease NMDA receptor conductance and related disturbances. Targeting the glycine site of NMDA receptors may represent a new strategy for tackling the core symptoms of ASD and this option deserves further study (Ghanizadeh, 2011). Studies of the safety and efficacy of using AMPA modulators as a primary treatment, as well as an add-on adjuvant, are recommended since only very scarce data are available. Finally, a recent controlled trial demonstrated that NAC had a significant impact on reducing irritability in children and adolescents with ASD. A double mechanism of action of NAC was noted, describing both its antioxidative properties and those of a glutamatergic agent. In addition, the use of NAC in young children is already diffuse and it has been found to be a safe mucolytic medication for children. If these promising features can be replicated, NAC would be an appealing medication for the treatment of behavioral problems in autism. Overall, efforts at clinical investigations for new ASD treatments are still unsatisfactory and the many needs of this vulnerable population are mostly unmet. However, potential new treatments are still a priority. Further research is needed to demonstrate whether glutamatergic agents could be an additional option for pharmacological intervention in children and adolescents with ASD