Review
Glutamate mediated signaling in the pathophysiology of autism spectrum disorders

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Abstract

Autism spectrum disorder (ASD) is a childhood neurodevelopmental disorder. During fetal and neonatal brain development, the cues for neurodevelopment are regulated in a well orchestrated manner. Generally, neurotransmitters play a major role in the formation of central nervous system (CNS) and peripheral nervous system (PNS). Glutamate, the excitatory neurotransmitter actively participates in various neurodevelopmental processes through complex regulatory events. Excitatory neurotransmitter signaling via glutamate receptors modulates cognitive functions such as memory and learning, which are usually impaired in ASD. Therefore, glutamate and its regulatory molecules are considered as potential targets for these disorders. Pharmacological, biochemical and behavioral studies reveal possible involvement of glutamatergic system in ASD pathology. An abnormal increase in electrical activity resulting from excessive glutamate signaling causes prolonged alterations in behavior, as commonly seen in ASDs. On the contrary, reports on animal models of hypoglutamatergia demonstrate phenotypes that overlap with features seen in autism. So controversies prevail whether to regard autism as hyper- or hypo-glutamatergic disorder. This paper reviews the role of glutamate and its regulatory proteins such as different receptors, transporters and metabolizing enzymes in the pathophysiology of ASD based on evidences gathered through multidisciplinary approaches. All these information raise the possibility of exploiting glutamatergic neurotransmitter system for future therapeutic interventions for ASD.

Highlights

Glutamate signalling is implicated in autism spectrum disorders. ► Glutamatergic system plays important role in neurodevelopment. ► Abnormal neurodevelopment leads to autistic phenotype. ► Various mechanisms regulate glutamate signalling. ► Knowledge on glutamate pathways may lead to biomarker/ drug development for autism.

Introduction

Autism is the prototypical form of pervasive developmental disorders (PDDs), characterized by complex behavioral impairments detectable as early as 18–36 months of age. Deficits are often manifested in domains such as social interaction, communication, and are also associated with stereotypic, repetitive and restrictive behavior and interests. Besides autism, PDDs include disorders such as Asperger's syndrome, pervasive developmental disorder-not-otherwise specified (PDD-NOS), Rett's disorder and childhood disintegrative disorder (American Psychiatric Association, 1994). Asperger's syndrome and PDD-NOS are phenotypically related to autistic disorder and have varying degrees of severity. Therefore, they are classified under the broad definition of autism and are collectively known as autism spectrum disorders or ASDs.

Autism has been considered to be a rare disorder till two decades back, but the recent epidemiological studies on American and European populations show a steep increase in its prevalence (Chakrabarti and Fombonne, 2001, Fombonne, 2003). A recent study on school-aged children in Canadian population reveal the prevalence rate of PDD and narrow diagnosis of autism to be close to 1% and 0.25% respectively (Lazoff et al., 2010). The increased prevalence rate possibly reflects broadening of the autism concept and improved diagnostic as well as detection criteria (Fombonne, 2003). There exists a sex bias in the incidence of autism with four times more males affected than the females (Abrahams and Geschwind, 2008), which raises the possibility of major involvement of X-chromosomal genes in its etiology. Two previous genome scan studies provided a moderate evidence of linkage to X chromosome (Liu et al., 2001); (Shao et al., 2002). But, the results of multivariate analysis of phenotypic expression that has been conducted within families do not support any linkage to X-chromosome under a multifactorial model (Pickles et al., 2000). Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4 have been highlighted as autism risk genes, but the low frequency of the mutations in these genes does not support them to be major contributors for the sex bias in autism etiopathogenesis (Jamain et al., 2003, Vincent et al., 2004). Furthermore, there are reports that suggest lack of any major effects of genes on the X-chromosome (Schultz and Klin, 2002). Even though, the disease mechanism has not yet been elucidated, the family and twin studies demonstrate that ASD is a complex multifactorial disorder involving many genes.

Approximately 6% of the cases with autistic traits have known etiologies that include fragile-X syndrome, neurofibromatosis, and tuberous sclerosis, etc. (Fombonne, 2002). But in majority of the cases the pathology is still a mystery. Different statistical models based on family studies indicate that at least fifteen genes with epistatic interaction are involved as predisposing factors (Jones and Szatmari, 2002, Pickles et al., 1995) besides unidentified non-genetic elements (Muhle et al., 2004). Concurrently, genomewide mapping studies identified several autism susceptibility regions throughout the genome (Gupta and State, 2007, Muhle et al., 2004, Weiss et al., 2009). Some chromosomal regions like 7q and 17q have been replicated in many studies as autism susceptibility loci (Benayed et al., 2005, Campbell et al., 2006, Devlin et al., 2005, Philippe et al., 1999, Yonan et al., 2003).

Biochemical and pharmacological studies have unveiled dysfunction of various neurotransmitter systems as causing autism. Major neurotransmitters that are implicated in autism include serotonin, dopamine, glutamate, GABA, etc. (Burgess et al., 2006, Lam et al., 2006, Rolf et al., 1993). Among these, glutamate has been shown to be directly involved in general cognitive functions such as memory and learning (Manent and Represa, 2007). Receptors of glutamate have also been extensively studied as potential candidates for several neurological and psychiatric diseases (Blandini, 2010, Moldrich et al., 2001, Nicoletti et al., 2011, Richards et al., 2010). In the case of autism, it has been proposed as a hypoglutamatergic disorder based on the neuroanatomical studies and the similarities between symptoms produced by glutamate antagonists in healthy and autistic subjects (Carlsson, 1998). Furthermore, animal models of hypoglutamatergia exhibit behavioral phenotypes as seen in autism, such as defective habituation, restricted behavioral repertoire and inability to change behavioral paradigm (Nilsson et al., 2004). Moreover, changes in the glutamate concentration have been demonstrated in autistic patients in comparison to controls, with high levels in plasma and low levels in platelets (Aldred et al., 2003, Fatemi, 2008). Information on direct involvement of abnormalities in glutamate receptor genes and deregulation of glutamatergic pathway in ASD pathophysiology are also available (Gupta and State, 2007, Jamain et al., 2002, Purcell et al., 2001, Serajee et al., 2003).

In this article we review the importance of glutamate in CNS development and the ways by which the perturbations in the functioning of glutamatergic system leads to autistic pathology. We also briefly review current evidences that substantiate participation of glutamate signaling in the pathophysiology of ASD and discuss whether the existing knowledge on glutamate mediated signaling and its regulation can be translated to design therapeutic strategies for ASD.

Section snippets

Involvement of neurotransmitters in neurodevelopment

Defects in neurodevelopment have an adverse effect on various brain functions. Neurotransmitters, the neuronal signaling molecules play an important role in the normal development of the brain, and are also important for maintaining functions such as memory, learning, behavior, motor activity, etc. Neurotransmitter mediated signaling is initiated by the binding of specific neurotransmitters to its receptor proteins on the post-synaptic membrane, the number of which varies for each

Overview of glutamate receptors

Glutamate is the principal excitatory neurotransmitter in brain and acts via two types of receptors: metabotropic and ionotropic receptors. Metabotropic glutamate receptors (GRM) are G-protein coupled receptors. These are membrane bound receptors, activated by the ligand and are involved in intracellular signal transduction, mediated via interaction with G-proteins (Kew and Kemp, 2005). There are three groups of metabotropic glutamate receptors, which are classified as: Groups I (GRM or mGluR 1

Glutamate transporters

Glutamate transporters are essential component of the glutamate mediated neurotransmitter signaling and they regulate the synaptic level of glutamate, which helps in preventing excitotoxicity. Excitotoxicity results from persistent and uncontrolled neuronal activation causing damage to target neurons. Five types of glutamate transporters are known to occur, which differ slightly in their function and localization. Two types (glial glutamate and aspartate transporter, GLAST/EAAT1 and glial

Glutamate signaling in CNS

Upon excitation of the pre-synaptic neuron, glutamate is released from the synaptic vesicle into the synaptic cleft when the vesicles are fused with the membrane of pre-synaptic neurons. The released glutamate binds to ionotropic (NMDAR, AMPAR) or metabotropic receptors (mGluR) expressed on the post-synaptic neurons. Binding of glutamate to mGluRs triggers activation of G-protein-dependent intracellular signaling cascade. Activation of ionotropic glutamate receptors AMPA, kainate, and NMDA by

Glutamate and GABAergic system in CNS

While glutamate regulates excitatory synaptic transmission, γ-aminobutyric acid (GABA) is involved in inhibitory neurotransmission. Equilibrium between excitatory and inhibitory neurotransmissions is always maintained in the brain to avoid many of the pathological conditions. Glutamatergic synapses release glutamate, which is predominantly taken up by astrocytes, where it gets amidated to glutamine by astrocyte-specific enzyme glutamine synthetase. It has been shown that transgenic mice lacking

Glutamate signaling in neurodevelopment

Glutamatergic signaling plays an important role in regulating neuronal migration, differentiation, neurite outgrowth, synaptogenesis and neuron survival in the developing brain (Elias et al., 2008, Georgiev et al., 2008, Komuro and Rakic, 1993, Manent and Represa, 2007). It is largely facilitated through Ca2+ gating. Blockade of NMDA receptors during the prenatal period using dizocilpine, phencyclidine or ethanol can induce apoptosis in vulnerable neurons. Glutamate also plays essential roles

Glutamate signaling in autism

Autism is a neurodevelopmental disorder with severe social deficits. Several lines of evidence suggest that abnormalities in glutamatergic signaling pathways occur in autism. Glutamate function in the CNS is linked not only to synaptic neuronal interactions, but also to other roles including brain maturation and cortical organization (Manent and Represa, 2007, Wijetunge et al., 2008). Glutamate receptors are mainly concentrated in regions that have been repeatedly implicated in autism,

Involvement of glutamate signaling molecules in ASD pathology

Genome wide scan studies have shown evidences of linkage of autism to the chromosome 7q21–32 region (IMGSAC, 2001). Chromosome 7q31 region contains metabotropic glutamate receptor 8 (GRM8) gene, which is a good positional and functional candidate for susceptibility to autism. Glutamate mediated signaling is negatively regulated by GRM8 through inhibition of glutamate release at the synapses. Therefore, this receptor indeed plays a role in preventing neuronal hyperexcitability and maintaining

Glutamate based therapeutic intervention for autism

Many children with autism spectrum disorder have a hyperexcitability in the brain triggered by glutamate. This may be caused by higher level of glutamate in the synapses and/or by the overexpression of its receptors. A double-blind, placebo-controlled, parallel group study in 28 children with primary diagnosis of autism with lamotrigine, a drug that modulates glutamate release showed that the children exhibited improvements in severity and behavioral features of autistic disorder, language and

Concluding remarks

The above review establishes the intricate relationship between autism, a neurodevelopmental disorder and glutamate, a major excitatory neurotransmitter. The various regulatory proteins of the glutamatergic system, which includes glutamate receptors (like GluR6, GluR8, NMDA, AMPA1 and 2 glutamate receptors) as well as glutamate transporters (like glial glutamate transporters, GLT1, GLAST, SLC1A1 and EAAT-1,2) are highly implicated in the pathophysiology of the disorder. But, the exact mechanism

Acknowledgments

PRC and SL are Research Associates of Department of Biotechnology, Government of India.

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