Fatma Sabukazan1, Oytun Erbaş1

1ERBAS Institute of Experimental Medicine, Illinois, USA & Gebze, Türkiye

Keywords: Astrocyte, autism spectrum disorder, glial cell, neuron

Abstract

To date, the cellular mechanisms underlying autism spectrum disorders (ASDs) have not been fully understood. However, various genetic and environmental factors contribute to the etiology of this developmental disorder. Astrocytes are abundant glial cells that perform various functions in health and disease in the central nervous system. Astrocyte dysfunction is found in many diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and neuropsychiatric disorders. Increasing evidence suggests that astrocytes play an important role in synapse maturation and function, and there is evidence of deficiencies in glial cell function in ASD, suggesting a link between astrocytes and autism. The aim of this review is to understand astrocyte functions and their contribution to ASD.

Autism is a developmental disorder of the central nervous system (CNS) characterized by stereotyped and repetitive movements, impaired social interaction, language, and non-verbal communication. It starts in early childhood and can have changing clinical symptoms over time, lasting throughout a person’s life with varying degrees of severity.[1] Autism spectrum disorders (ASDs) are classified into two main categories: deficits in social communication and interaction, and repetitive behaviors and restricted activities. Additionally, digestive problems, epilepsy, immune problems, sleep disorders, negative mental states (depression and anxiety), and mitochondrial dysfunction can also develop in ASD.[2-3] This disorder affects many parts of the brain (dorsal and medial prefrontal cortex, superior temporal cortex, and amygdala), but it is not well understood how this effect develops. Parents typically notice this condition in their children within the first two years of life. Early behavioral or cognitive interventions can help children develop self-care abilities and social and communication skills.[4]

In 1943, American child psychiatrist Leo Kanner[5] named autism early childhood autism. Kanner used the same term to describe the characteristics of eleven children exhibiting similar behavioral patterns and reported autism as a syndrome with problems in emotional contact and interpersonal relationships in his article. Describing a clinical picture that includes delayed speech, repetitive behaviors, poor eye contact, communication problems, and unusual interests and abilities, Kanner stated that autism is a congenital disease.Autism has a prevalence of 12-15% worldwide.[6-7] According to a study, autism is present in every 59th child. Autism is three to four times more common in boys than in girls, and many girls show less prominent features than boys.[8] It is genetically very heterogeneous and is seen to be associated with many genetic mutations, most of which are probably rare causal variants.[9]

The genetic heterogeneity of autism has made it difficult to identify specific genes related to the disease and has therefore hindered efforts to investigate disease mechanisms. Recent findings on the changing genetic pathways in ASD have been obtained from studies of syndromic disorders with a high incidence of autism caused by mutations in a single gene, including Rett syndrome (RTT) and Fragile X (FXS) syndrome.[10]

Fragile X Syndrome

Fragile X syndrome is the most common cause of familial mental retardation in males, after Down syndrome, and can lead to intellectual disability.[11] The Fragile X mental retardation (FMR) protein plays an important role in neuronal development, synaptic transmission, and elasticity. Therefore, when the FMR protein is not produced at all or is significantly reduced, neuronal involvement occurs.[12] Obsessive-compulsive disorder and anxiety disorder are common symptoms. The incidence of autism is much higher in males with FXS than in the general population.[13]

Rett Syndrome

Rett Syndrome occurs due to mutations in the methyl-CpG binding protein 2 (MECP2) gene. The MECP2 gene located in the Xq28 region encodes the MeCP2 protein. MeCP2 protein is most abundant in the brain.[14] One of the most challenging aspects of RTT is complex and tonic-clonic seizures.[15] Abnormalities such as teeth grinding, screaming episodes, anxiety attacks are seen in RTT patients and there is no known cure.[16-18] In RTT mouse models, desipramine, a norepinephrine inhibitor, has been observed to alleviate breathing in MeCP2 mutant mice, but no improvement was observed in clinical trials.[19-21]

Neurodevelopmental Disorders and Autism

Neurodevelopmental genes are an important factor to consider, as functional and anatomical movements associated with defects in these genes during brain development can trigger the onset of neurodevelopmental disorders in childhood, including ASD.[22-23] Genes associated with neurodevelopmental disorders can be grouped into three broad categories: those related to synapse structure and activity, those related to protein synthesis, and those involved in regulating gene expression. Many of these genes code for proteins with a clear synaptic function, making the pathological features of neurodevelopmental disorders ‘neurocentric’. Therefore, it is anticipated that genetics alone may not be able to explain all cases of autism. Exposure to a range of non-heritable environmental factors in addition to a specific combination of autism-related genes can significantly influence susceptibility to autism and the variable expression of autism-related traits.[24]

Translation: In studies conducted with children and adolescents for the treatment of neurodevelopmental disorders, risperidone, and aripiprazole have been used, and in the majority of cases, improvement has been observed in irritability, self-harm, repetitive behaviors, and aggression.[25] In a study where oxytocin was applied to a small sample of individuals with autism, positive effects on social behavior were observed, which suggests that oxytocin may be effective in the symptomatic treatment of neurodevelopmental disorders.[26-28]

ASTROCYTES

Astrocytes are the most common glial cells in the CNS, which are considered the cornerstone of brain cytoarchitecture and function, along with neurons and oligodendrocytes.[29] It is known that they constitute 20-40% of all glial cells. Astrocytes are derived from neuroectoderm.[30] Astrocytes actively participate in neuronal metabolism, synaptic plasticity, and neuroprotection. They regulate blood flow by releasing various mediator molecules (nitric oxide, prostaglandins) that dilate and constrict blood vessels. Astrocytic processes surround all major synapses to ensure fluid, ion, and pH homeostasis for synaptic transmission. Additionally, astrocytes express functional neurotransmitter receptors at the synaptic level and release various neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), and adenosine triphosphate (ATP) via Ca+2-dependent exocytosis.[31-34]

Therefore, there is an increase in the expression of glial fibrillary acidic protein (GFAP) in response to neuronal damage.[35] Reactive astrocytes have been identified as potential therapeutic targets for certain disease contexts, where molecular dissection can help identify molecules that can enhance or block their functions. For example, a molecule called parawixin 1, isolated from spider venom, has been shown to protect retinal neurons from ischemic degeneration by increasing the function of the excitatory amino acid transporter-2 (EAAT-2), which increases glutamate uptake and thus reduces the potential for glutamate excitotoxicity.[36]

Astrocytes can make contact with multiple neurons and up to 100,000 synapses.[37] They have receptors and ion channels found in neurons, allowing them to detect and respond to a variety of neuronal signals. Astrocytes and microglial cells play an important role in the elimination process of synaptic connections, which is a structural formation and elimination process. They are vital in controlling and improving the connectivity of mature neuronal circuits. For example, in developing brains, astrocytes can physically eliminate synapses via phagocytic pathways, such as multiple epidermal growth factor-like domains 10 (MEGF10) and c-Mer proto-oncogene tyrosine kinase (MERTK).[38-40]

Astrocytes release a variety of neuroactive substances, including growth factors and gliotransmitters. Glutamate is an essential amino acid that plays a role in synaptic transmission. Mutations in glutamate receptors found in peripheral organs, tissues, and endocrine cells can result in the development of neuropsychiatric disorders.[41]

Overall, these studies suggest that the physiological interactions between astrocytes and synapses are essential for synapse formation and network functioning. Loss, deviation, or functional impairment of astrocytes and microglia may contribute to the pathogenesis and progression of autism. Astrocyte dysfunction is seen in a number of diseases, including multiple sclerosis, Alzheimer’s disease, Huntington’s disease, and neuropsychiatric disorders.

ASTROCYTIC ROLES IN GLUTAMATE AND GLUTAMATE TRANSPORTERS

Glutamate is the main excitatory neurotransmitter in the CNS, responsible for fast excitatory neurotransmission.[42] Five subtypes of glutamate transporters have been cloned to date. Three of these glutamate transporters were initially identified in the mouse brain: glutamate aspartate transporter (GLAST), glutamate transporter 1 (GLT-1), and excitatory amino acid carrier 1 (EAAC1). Their human homologs are EAAT1, EAAT2, and EAAT3, respectively. The remaining two human and rodent subtypes, EAAT4 and EAAT5, share common terminology.[43] All five transporters are localized differently among various brain structures. GLAST immunostaining and protein expression are most prominent in the cerebellum, with intermediate levels in other structures such as the hippocampus and frontal cortex. In contrast, GLT-1 expression is primarily found in the cerebellum with low levels of expression in the frontal cortex.[44] Both of these transporters represent the most prominent “astrocytic” transporters, localized at the astroglial membrane or in Bergmann glia associated with excitatory synapses. EAAT3 is expressed at low levels in different regions of the brain. The remaining transporters, EAAT4 and EAAT5, are expressed only in the cerebellum and retina, respectively.[45-46] Rapid removal of glutamate from the extracellular space is necessary for the survival and normal function of neurons. While all CNS cell types express glutamate transporters, astrocytes are primarily responsible for glutamate uptake.[47] Astrocytes mediate glutamate uptake through both Na+-independent and Na+-dependent systems. Na+-dependent glutamate transporters in astrocytes were originally cloned from the mouse brain and named GLAST and GLT-1.[48] Transporter activity is normally regulated at multiple levels, including protein expression, surface trafficking, protein binding, phosphorylation, and other direct modifications. [49-50]

ASTROCYTE GENE MUTATIONS

There are several examples of genetic mutations that lead to astrocyte dysfunction. The first example is a dominant mutation in the GFAP gene, which is exclusively expressed by astroglia in the CNS, causing Alexander’s disease. Patients with this macrocephaly exhibit severe disease dysfunction, seizures, psychomotor disturbances, and early. Another example is a dominant gain-of-function mutation in the gene encoding superoxide dismutase, which leads to the production of toxic molecules for motor neurons and causes a familial form of amyotrophic lateral sclerosis.[51-53]

GFAP is a member of the intermediate filament protein family that serves cytoarchitectural functions, along with vimentin, nestin, and others and is a marker for the immunohistochemical identification of astrocytes.[54]

EFFECT OF ASTROCYTES ON NEURODEVELOPMENTAL DISORDERS

There are several genetic mutations that can cause astrocyte dysfunctions. The dominant mutation of the GFAP gene, which is expressed only by astroglia in the CNS, causes Alexander’s disease. Patients with this macrocephaly exhibit severe disease impairment, seizures, psychomotor disturbances, and early. Another example is a familial form of amyotrophic lateral sclerosis caused by a gain-of-function mutation in the gene encoding superoxide dismutase, which produces molecules toxic to motor neurons. Astrocytes are part of the intermediate filament protein family, serving cytoskeletal functions, including GFAP, vimentin, nestin, and others, and are markers used for immunohistochemical identification of astrocytes. The first evidence of potential astrocyte abnormalities in neurodevelopmental disorders came from the biochemical analysis of brain samples of patients with ASD and from screening genetic risk factors for various neurodevelopmental disorders. Astrogliosis, demonstrated by increased GFAP expression, was found in the cerebellar cortex of brains with ASD, but neuronal degeneration was not usually observed in the brains of neurodevelopmental disorder patients. Several other astroglial protein expression changes were also observed in the brain samples of patients with ASD, including increased EAAT2 and EAAT1 in the cerebellum, significantly increased connexin 43 in the superior frontal cortex, and decreased aquaporin 4 in the cerebellum.[55-57] These astroglial changes suggest that astrocytes may be involved in neurodevelopmental disorders. Genetic studies have identified specific nucleotide polymorphisms in the EAAT1 sequence that are associated with the severity of repetitive behaviors and anxiety in children with ASD.[58] Despite the results of these clinical studies, it is important to note that specific mechanisms involving astrocytes in the pathogenesis of neurodevelopmental disorders are still being identified.

Changes in astrocytes have been observed in patients with ASD and animal models. However, it is not clear whether astrocyte dysfunction in mice is causal or dependent on ASD-like phenotypes. The role of neurons in the pathogenesis of ASD has been a broad research topic. The expression of astrocyte markers such as GFAP, aquaporin-4, connexin 43, and EAAC1 has been altered in postmortem brain tissue from ASD-affected donors.[59-62] Astrocytes derived from control sources rescue the morphological and synaptic defects of ASD neuronal cultures. Astrocytes, the most abundant glial cells in the CNS, contribute to many critical brain functions such as neurogenesis, synaptic development, synaptic transmission, and plasticity during early development and adulthood and regulate their behaviors under both physiological and pathological conditions. Astrocyte-derived ATP plays a role in modulating ASD-like behaviors in mice.[63-66]

Although ASD is generally considered a neurodevelopmental syndrome, recent studies have shown that dysfunction in autism risk genes during both early development and adulthood leads to reversible autism-like phenotypes in adult animals when the normal functions of these risk genes are restored. Observations that the behavioral and physiological deficits in animal models of ASD are reversed upon pharmacological or genetic manipulation, together with the autism synaptic theory, suggest that a continuing synaptopathy may underlie the cause of ASD. Overall, astrocytes play a role in the pathogenesis of ASDs. Astrocytes can release various synaptic transmitters and modulators, including glutamate, D-serine ATP/adenosine, GABA, and lactate, through calcium-dependent and independent signaling pathways, but not limited to these. [67-71]

NEUROANATOMICAL FINDINGS IN AUTISM SPECTRUM DISORDERS

One of the most important theories regarding the neuropathology of ASDs is the abnormal growth of the amygdala, frontal and temporal cortex during development, which then slows down with age.[72] The main causes of this are thought to be neurogenesis, excessive dendritic growth, and inflammatory responses that lead to microglial activation.[73]

There may be three cellular factors to explain the excessive brain growth in autism:

Number of neurons: An increase in the number of neurons is not the only factor that can explain the accelerated cortical growth in autism.

Neuronal dendritic growth and the number of synapses: Neuronal dendritic growth and increased numbers of synapses are the closest possibilities for excessive early brain growth in autism. If dendrites grow excessively or do not reach the same level as active synaptic protrusions, abnormal connections may occur between neurons. However, only a small number of postmortem studies have examined neuronal dendritic connections or synapses related to autism. Numbers and sizes of glial cells: Gliogenesis has differences among microglia, oligodendrocytes, and astrocytes from a prenatal perspective. Astrocytes constitute 17% of the glia in the brain. If glia is responsible for the increase in cerebral volume in autistic children, a neuroinflammatory response involving microglia could be the likely culprit. All of these factors result in the overall brain growth seen in autism.[74-76]

In conclusion, until very recently, the role of glial cells at the onset of ASD was overlooked, and therefore, pharmacological strategies aimed almost exclusively at neuronal activity and synaptic transmission to treat symptoms. However, accumulating evidence suggests that astrocytes and microglia may play a significant role in the regulation of synapse formation, function, and elimination, and therefore may have an impact on ASD. Recent data suggest that ASD is at least partially caused by disorders affecting glial cells or neuron-glia interactions, and future pharmacological research should consider the possibility of improving glial cell functions. By including more patients and control groups in studies, and developing biomarkers that can be used in the diagnosis and prognosis of autism, the disease process can be positively affected. This review shows that differences in glial cells, such as astrocytes, and disruptions in their functions, can have an impact on the ASD process. Although research on the molecular mechanisms of astroglial maturation and how the disruption of this maturation process contributes to the pathogenesis of neurodevelopmental disorders continues, the availability of new in vivo tools for studying astrocytes can be of great benefit in answering these questions. Understanding the role of astroglia in the pathogenesis of neurodevelopmental disorders will facilitate the search for treatments for these disorders. Future studies should shed light on differentiating between pathological processes underlying the core processes of autism and findings related to the cause of death or comorbidities.

Cite this article as: Sabukazan F, Erbaş O. Astrogliosis: Glial Perspective of Autism Spectrum Disorders. JEB Med Sci 2023;4(1):45-51.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Financial Disclosure

The authors received no financial support for the research and/or authorship of this article.

References

  1. Filipek PA, Accardo PJ, Baranek GT, Cook EH Jr, Dawson G, Volkmar FR, et al. The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord. 1999 Dec;29:439-84.
  2. Petersson M, Lundeberg T, Sohlström A, Wiberg U, Uvnäs-Moberg K. Oxytocin increases the survival of musculocutaneous flaps. Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357:701-4.
  3. Yücel U, Kahramanoğlu İ, Altuntaş İ, Erbaş O. Effect of mitochondrial dysfunction and oxidative stress on the pathogenesis of autism spectrum disorders. D J Tx Sci 2021;6:73-85.
  4. Sanchack KE, Thomas CA. Autism Spectrum Disorder: Primary Care Principles. Am Fam Physician. 2016 Dec 15;94:972-9.
  5. Kanner L, Eisenberg L. Early infantile autism, 1943-1955. Psychiatr Res Rep Am Psychiatr Assoc. 1957 Apr;:55-65.
  6. Masi A, DeMayo MM, Glozier N, Guastella AJ. An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options. Neurosci Bull. 2017 Apr;33:183-93.
  7. Kanner L. Autistic disturbances of affective contact. Acta Paedopsychiatr. 1968;35:100-36.
  8. Sasani H, Erbaş O. Microglial Effects on Psychiatric Disorders. JEB Med Sci 2022;3:26-34.
  9. Howlin P, Goode S, Hutton J, Rutter M. Adult outcome for children with autism. J Child Psychol Psychiatry. 2004 Feb;45:212-29.
  10. Murdoch JD, State MW. Recent developments in the genetics of autism spectrum disorders. Curr Opin Genet Dev. 2013 Jun;23:310-5.
  11. Parikshak NN, Won H, Lowe JK, Chandran V, Horvath S.Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013 Nov 21;155:1008-21.
  12. Saldarriaga W, Tassone F, Gonzalez-Teshima LY, Forero-Forero JV, Ayala-Zapata S, Ha- german R. Fragile X syndrome. Colombia Medica 2014;45:190-8.
  13. Crawford DC, Acuña JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001 Sep-Oct;3:359-71.
  14. Berry-Kravis E. Epilepsy in fragile X syndrome. Dev Med Child Neurol. 2002 Nov;44:724-8.
  15. Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014 Mar;51:152-8.
  16. Jian L, Bower C, Anderson A, Williamson S, Christodoulou J, Leonard H, et al. Predictors of seizure onset in Rett syndrome. J Pediatr. 2006 Oct;149:542-7.
  17. Karaguzel G, Holick MF. Diagnosis and treatment of osteopenia. Rev Endocr Metab Disord. 2010 Dec;11:237-51.
  18. Vialle R, Thévenin-Lemoine C, Mary P. Neuromuscular scoliosis. Orthop Traumatol Surg Res. 2013 Feb;99:S124-39.
  19. Mount RH, Hastings RP, Reilly S, Cass H, Charman T. Behavioural and emotional features in Rett syndrome. Disabil Rehabil. 2001 Feb 15-Mar 10;23:129-38.
  20. Roux JC, Dura E, Moncla A, Mancini J, Villard L. Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome. Eur J Neurosci. 2007 Apr;25:1915-22.
  21. Zanella S, Mebarek S, Lajard AM, Picard N, Dutschmann M, Hilaire G, et al. Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model. Respir Physiol Neurobiol. 2008 Jan 1;160:116-21.
  22. Mancini J, Dubus JC, Jouve E, Roux JC, Franco P, Lagrue E, et al. Effect of desipramine on patients with breathing disorders in RETT syndrome. Ann Clin Transl Neurol. 2017 Dec 27;5:118-27.
  23. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome. Am J Respir Cell Mol Biol. 2014 Jun;50:1031-9.
  24. Pala HG, Erbas O, Pala EE, Artunc Ulkumen B, Akman L, Akman T, et al. The effects of sunitinib on endometriosis. J Obstet Gynaecol. 2015 Feb;35:183-7.
  25. Toma C, Hervás A, Torrico B, Balmaña N, Salgado M, Maristany M, et al. Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2. Psychiatr Genet. 2013 Apr;23:82-5.
  26. Pessah IN, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van De Water J, et al. Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology. 2008 May;29:532-45.
  27. Owen R, Sikich L, Marcus RN, Corey-Lisle P, Manos G, McQuade RD, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009 Dec;124:1533-40.
  28. Fung LK, Mahajan R, Nozzolillo A, Bernal P, Krasner A, Veenstra-Vander Weele J, et al. Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics. 2016 Feb;137 Suppl 2:S124-35.
  29. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010 Apr 1;67:692-4.
  30. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Verkhratsky A, et al. Glial cells in (patho)physiology. J Neurochem. 2012 Apr;121:4-27.
  31. Ekmekçi AM, Erbaş O. The role of intestinal flora in autism and nutritional approaches. D J Tx Sci 2020;5:61-9.
  32. Matta SM, Hill-Yardin EL, Crack PJ. The influence of neuroinflammation in Autism Spectrum Disorder. Brain Behav Immun. 2019 Jul;79:75-90.
  33. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Hediger MA, Wang Y, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996 Mar;16:675-86.
  34. Fontana AC, Ferreira Dos Santos W, Coutinho-Netto J, Grutle NJ, Watts SD, Danbolt NC, et al. Enhancing glutamate transport: mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Mol Pharmacol. 2007 Nov;72:1228-37.
  35. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002 Jan 1;22:183-92.
  36. Fiacco TA, McCarthy KD. Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia. 2006 Nov 15;54:676-90.
  37. Durankuş F, Albayrak Y, Erdoğan F, Albayrak N, Erdoğan MA, Erbaş O, et al. Granulocyte colony-stimulating factor has a sex-dependent positive effect in the maternal immune activation-induced autism model. Int J Dev Neurosci. 2022 Dec;82:716-26.
  38. Nakamura H, O'Leary DD. Inaccuracies in initial growth and arborization of chick retinotectal axons followed by course corrections and axon remodeling to develop topographic order. J Neurosci. 1989 Nov;9:3776-95.
  39. Chung WS, Clarke LE, Wang GX, Stafford BK, Smith SJ, Barres BA, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013 Dec 19;504:394-400.
  40. Jean YY, Lercher LD, Dreyfus CF. Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway. Neuron Glia Biol. 2008 Feb;4:35-42.
  41. Lee HG, Wheeler MA, Quintana FJ. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov. 2022 May;21:339-58.
  42. Sever IH, Ozkul B, Bozkurt MF, Erbas O. Therapeutic effect of finasteride through its antiandrogenic and antioxidant role in a propionic acid-induced autism model: Demonstrated by behavioral tests, histological findings and MR spectroscopy. Neurosci Lett. 2022 May 14;779:136622.
  43. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A, et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001 Jan;27:117-20.
  44. Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci. 2007 Nov;10:1355-60.
  45. Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG, et al. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci. 1994 Sep;14:5559-69.
  46. Kanai Y, Hediger MA. The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol. 2003 Oct 31;479:237-47.
  47. Özkul B, Urfalı FE, Sever İH, Bozkurt MF, Söğüt İ, Elgörmüş ÇS, et al.Demonstration of ameliorating effect of vardenafil through its anti-inflammatory and neuroprotective properties in autism spectrum disorder induced by propionic acid on rat model. Int J Neurosci. 2022 Nov;132:1150-64.
  48. Beart PM, O'Shea RD. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol. 2007 Jan;150:5-17.
  49. Fairman WA, Amara SG. Functional diversity of excitatory amino acid transporters: ion channel and transport modes. Am J Physiol. 1999 Oct;277:F481-6.
  50. Kanai Y, Hediger MA. The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol. 2003 Oct 31;479:237-47.
  51. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000 Oct;32:1-14.
  52. Sonnewald U, Qu H, Aschner M. Pharmacology and toxicology of astrocyte-neuron glutamate transport and cycling. J Pharmacol Exp Ther. 2002 Apr;301:1-6.
  53. Bunch L, Erichsen MN, Jensen AA. Excitatory amino acid transporters as potential drug targets. Expert Opin Ther Targets. 2009 Jun;13:719-31.
  54. Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE. Alexander disease. J Neurosci. 2012 Apr 11;32:5017-23.
  55. Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum. 2005;4:206-10.
  56. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001 Nov 13;57:1618-28.
  57. Fatemi SH, Folsom TD, Reutiman TJ, Lee S. Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse. 2008 Jul;62:501-7.
  58. Bons D, van den Broek E, Scheepers F, Herpers P, Rommelse N, Buitelaar JK, et al. Motor, emotional, and cognitive empathy in children and adolescents with autism spectrum disorder and conduct disorder. J Abnorm Child Psychol. 2013 Apr;41:425-43.
  59. Uyanikgil Y, Özkeşkek K, Çavuşoğlu T, Solmaz V, Tümer MK, Erbas O, et al. Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci. 2016;126:70-5.
  60. Broek JA, Brombacher E, Stelzhammer V, Guest PC, Rahmoune H, Bahn S, et al. The need for a comprehensive molecular characterization of autism spectrum disorders. Int J Neuropsychopharmacol. 2014 Apr;17:651-73.
  61. Erbaş O, Solmaz V, Aksoy D. Inhibitor effect of dexketoprofen in rat model of pentylenetetrazol-induced seizures. Neurol Res. 2015;37:1096-101.
  62. Bae SM, Hong JY. The Wnt Signaling Pathway and Related Therapeutic Drugs in Autism Spectrum Disorder. Clin Psychopharmacol Neurosci. 2018 May 31;16:129-35.
  63. Ziats MN, Edmonson C, Rennert OM. The autistic brain in the context of normal neurodevelopment. Front Neuroanat. 2015 Aug 25;9:115.
  64. Cao X, Wang Q, Zhang M, Xiong WC, Yan HC, Gao YB, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013 Jun;19:773-7.
  65. Erta M, Giralt M, Esposito FL, Fernandez-Gayol O, Hidalgo J. Astrocytic IL-6 mediates locomotor activity, exploration, anxiety, learning and social behavior. Horm Behav. 2015 Jul;73:64-74.
  66. Nagai J, Rajbhandari AK, Gangwani MR, Hachisuka A, Coppola G, Masmanidis SC, et al. Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue. Cell. 2019 May 16;177:1280-1292.e20.
  67. Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005 Aug;6:626-40.
  68. Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum. 2005;4:206-10.
  69. Wang J, Li Z, Feng M, Ren K, Shen G, Zhao C, et al. Opening of astrocytic mitochondrial ATP-sensitive potassium channels upregulates electrical coupling between hippocampal astrocytes in rat brain slices. PLoS One. 2013;8:e56605.
  70. Choudhury PR, Lahiri S, Rajamma U. Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacol Biochem Behav. 2012 Feb;100:841-9.
  71. Hertz L, Peng L, Dienel GA. Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/ glycogenolysis. J Cereb Blood Flow Metab. 2007 Feb;27:219-49.
  72. Portis S, Giunta B, Obregon D, Tan J. The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome. Int J Physiol Pathophysiol Pharmacol. 2012;4:140-8.
  73. Jou MJ. Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes. Adv Drug Deliv Rev. 2008 Oct-Nov;60:1512-26.
  74. Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, et al. Mapping early brain development in autism. Neuron. 2007 Oct 25;56:399-413.
  75. Amaral GD, Schumann CM, Nordahl CW. Neuroanatomy of Autism. Trends in Neurosciences. 2008;31:137-45.
  76. Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neuronsin autism spectrum disorders. Brain Res. 2010;1309:83-94.