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Int. J. Devl Neuroscience xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Developmental Neuroscience

journal homepage: www.elsevier.com/locate/ijdevneu

1 The apoptotic perspective of autism

2 Q1 Hongen Wei a,∗ , Ian Alberts b , Xiaohong Li c
a
3 Central Laboratory, Shanxi Provincial People’s Hospital, Affiliate of Shanxi Medical University, Taiyuan, China
b
4 Department of Natural Sciences, LaGuardia CC, CUNY, New York, NY 11101, USA
c
5 Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA
6

7
20 a r t i c l e i n f o a b s t r a c t
8
9 Article history: Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction,
10 Received 5 April 2014 deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. The
11 Received in revised form 22 April 2014 normal brain development during fetal brain development and the first year of life is critical to the
12 Accepted 23 April 2014
behaviors and cognitions in adulthood. Programmed cell death (apoptosis) is an important mechanism
13 that determines the size and shape of the brain and regulates the proper wiring of developing neuronal
14 Keywords:
networks. Pathological activation of apoptotic death pathways under pathological conditions may lead
15 Autism
to neuroanatomic abnormalities and possibly to developmental disabilities. It has been demonstrated a
16 Apoptosis
17 Protein
possible association between neural cell death and autism. Here, the abnormal apoptosis found in autism
18 Signaling pathway from postmortem and animal studies was reviewed and the possible mechanism was discussed.
19 Mechanism © 2014 Published by Elsevier Ltd. on behalf of ISDN.

21 1. Introduction pathways, which are the mitochondrial, death receptor and inflam- 36

matory pathways (Jarskog et al., 2005). Excesses and deficits in 37

22 Autism is a common neurodevelopmental disorder. Typically neuronal numbers have been observed not only in typical neu- 38

23 diagnosed before three years old, autistic children usually present rodegenerative disorders such as Alzheimer’s and Huntington’s 39

24 with significant language delays, social and communication impair- diseases but also in several neurodevelopmental disorders, includ- 40

25 ments, as well as abnormal repetitive and restrictive behaviors ing schizophrenia and autism (Jarskog et al., 2005; Margolis et al., 41

26 (Nazeer and Ghaziuddin, 2012). Although the pathogenesis of 1994). 42

27 autism is not understood, emerging evidence points to apoptotic So far, there is relatively few of the neuropathology specific to 43

28 mechanisms being involved in this disorder. Programmed cell autism has been detected because of a limited amount of brain tis- 44

29 death, also termed as “apoptosis”, is an essential part of normal sue available for the neuropathologic study of autism (Silver and 45

30 development, particularly in the nervous system. Spatial, tempo- Rapin, 2012). However, earlier studies have shown that abnormal- 46

31 ral, or quantitative errors in the stimuli that initiate programmed ities occur in many areas of the autistic brain, including decreased 47

32 cell death, or errors within the programmed cell death pathway Purkinje cell counts in the cerebellar hemispheres and vermis, loss 48

33 itself, can result in an abnormal number of neurons and pathologi- of granular cells, and Purkinje cell atrophy (Bauman and Kemper, 49

34 cal neural development. The apoptosis mechanism in the central 1985, 2005; Kemper and Bauman, 2002; Ritvo et al., 1986). One 50

35 nervous system has been suggested to include three signaling study of postmortem brain tissues from autistic patients demon- 51

strate an active and ongoing neuroinflammatory process in the 52

cerebral cortex and white matter characterized by astroglial and 53

neuroglial activation (Vargas et al., 2005). Magnetic resonance 54

Abbreviations: Bcl-2, B-cell lymphoma 2; BDNF, brain-derived neurotrophic imaging (MRI) studies of total brain volume demonstrate that 55
factor; GABA, gamma-aminobutyric acid; GFP, green fluorescent protein; GM-
young children with autism have 5–10% abnormal enlargement in 56
CSF, granulocyte-macrophage colony-stimulating factor; IFN-␥, interferon-␥; IL,
interleukin; MAPK, mitogen-activated protein kinases; MCP, macrophage chemoat- brain volumes, compared to those of normal controls (Amaral et al., 57

tractant protein; MRI, magnetic resonance imaging; PBMCs, peripheral blood 2008). Reduced corpus callosum volume and increased amygdala 58
mononuclear cells; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin volume have also been reported in subjects with autism (Egaas 59
homolog; TNF-␣, tumor necrosis factor alpha. et al., 1995; Piven et al., 1997; Schumann et al., 2004; Sparks 60
∗ Corresponding author at: Central Laboratory, Shanxi Provincial People’s Hospi-
et al., 2002). In addition, multiple brain regions exhibit aberrant 61
tal, Affiliate of Shanxi Medical University, 29 Shuangta Road, Taiyuan 030012, China.
Tel.: +86 351 4960572; fax: +86 351 4961994. structural organization in children and adolescents with autism in 62

E-mail addresses: hongenwei@gmail.com, hongen.wei@hotmail.com (H. Wei). the structure MRI studies (Stigler et al., 2011; Uddin et al., 2011). 63

http://dx.doi.org/10.1016/j.ijdevneu.2014.04.004
0736-5748/© 2014 Published by Elsevier Ltd. on behalf of ISDN.

Please cite this article in press as: Wei, H., et al., The apoptotic perspective of autism. Int. J. Dev. Neurosci. (2014),
http://dx.doi.org/10.1016/j.ijdevneu.2014.04.004
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64 These pathological changes could involve altered apoptosis. In this 1996). Based on these findings, we reason that the increased apo- 124

65 review, we focus on discussion of abnormal apoptosis findings in ptosis and cathepsin D expression in the autistic brain could be 125

66 autism from postmortem and animal studies. induced by elevated levels of cytokines, and cathepsin D may be 126

involved in the mediation of apoptosis induced by the cytokines. 127

67 2. Apoptosis related proteins in autism

2.3. P53 128

68 2.1. Bcl-2
The tumor suppressor and transcription factor p53 is a key 129

modulator of cellular stress responses. Activation of p53 can trig- 130

69 Several studies implicate B-cell lymphoma 2 (Bcl-2) involve-
ger apoptosis in many cell types including neurons (Culmsee and 131
70 ment in neuropsychiatric disorders, including schizophrenia
Mattson, 2005). P53 mediates apoptosis through a linear path- 132
71 (Jarskog et al., 2000, 2005), bipolar disorder, major depression,
way involving bax transactivation and translocation, cytochrome 133
72 and lissencephaly (Hong et al., 2000). The study to examine the
c release from mitochondria and caspase activation. P53-mediated 134
73 potential role of apoptosis in autism firstly measured levels of the
apoptosis can be blocked by Bcl-2 family members regulating mito- 135
74 anti-apoptotic regulatory protein Bcl-2 in postmortem brain tis-
chondrial function and by caspase inhibitors (Shen and White, 136
75 sue. Quantification of Bcl-2 showed a significant 34–51% reduction
2001). One research group has demonstrated that the levels of p53 137
76 in autistic cerebellum compared with controls by western blotting
were increased by 130%, 67.5% and 38% in autistic parietal cortex, 138
77 (Fatemi et al., 2001a,b). The same group also investigated the levels
superior frontal and cerebellar cortices respectively when com- 139
78 of Bcl-2 in several important brain tissues of autistic subjects and
pared to control tissues. In addition, it has been shown that the 140
79 compared with age-, sex-, and postmortem-interval-matched nor-
Bcl-2/P53 ratio has a 64% reduction in autistic brain as compared 141
80 mal control subjects. In the autistic group, mean Bcl-2 values were
to controls in the same brain areas (Araghi-Niknam and Fatemi, 142
81 reduced by 32% in parietal cortex, albeit nonsignificantly when
2003; Fatemi and Halt, 2001). With immunohistochemistry studies, 143
82 compared to controls (Fatemi and Halt, 2001). The levels of Bcl-2
Sheikh et al. detected an increased p53 expression in the Purk- 144
83 decreased by 38% and 36% in autistic superior frontal and cerebellar
inje cells and granule cells in the cerebella of autistic brains in 145
84 cortices, respectively when compared to control tissues (Araghi-
comparison with the age-matched controls. However, no obvious 146
85 Niknam and Fatemi, 2003). Bcl-2 is a membrane-bound protein
differences in p53 expression were seen in the frontal cortices of 147
86 with a neuroprotective role in the central nervous system. Bcl-2
autistic subjects and control subjects (Sheikh et al., 2010b). 148
87 has been shown to inhibit apoptosis and enhance the survival of
88 neurons (Sasaki et al., 2006). Recently, Sheikh et al. (2010a,b) also
2.4. Caspase 149
89 found that the Bcl-2 expression was significantly reduced in the
90 frontal cerebral cortex and cerebellum of autistic subjects. Lym-
Caspases are cysteinyl aspartate-specific proteases that play a 150
91 phoblast cell lines have been suggested to be a valuable tool for
critical role in the regulatory and execution phases of apoptosis. 151
92 identifying genes associated with autism and provide an alterna-
Similar to classic neurodegenerative disorders such as Alzheimer’s 152
93 tive approach for understanding the biology and genetics of autism
and Parkinson’s diseases where high caspase-3 levels are found 153
94 (Baron et al., 2006; Wei et al., 2011). By examining Bcl-2 protein
in postmortem brain tissue (Hartmann et al., 2000; Masliah et al., 154
95 expression in the lymphoblasts of autistic subjects and compare
1998), Sheikh et al. (2010a) found that the expression of caspase- 155
96 the results with age-matched normal controls, Malik et al. identi-
3 was increased in the cerebellum of autistic subjects. However, 156
97 fied that Bcl-2 protein expression is also significantly decreased in
caspase-3 levels were essentially unchanged and actually trended 157
98 lymphoblasts of autistic subjects (Malik et al., 2011).
toward a slight decrease in schizophrenia temporal cortex (Jarskog 158

et al., 2004). Furthermore, it has been reported that Saudi autistic 159

99 2.2. Cathepsin D patients have a remarkable lower plasma caspase-3 compared to 160

age and gender matching controls (El-Ansary et al., 2011). Recent 161

100 Cathepsin D is a predominant lysosomal aspartic acid protease studies suggest that peripheral blood mononuclear cells (PBMCs) 162

101 abundantly expressed in the brain and hydrolyzes select peptide may represent a useful tool to investigate systemic neurochemi- 163

102 bonds of target proteins with high specificity. Cathepsin D initi- cal changes in neurodegenerative disease (Buttarelli et al., 2006). 164

103 ates apoptosis through caspase-8 and has been shown to play an The work by Siniscalco et al. (2012) showed an up-regulation and 165

104 important role in regulation of cellular apoptosis. It was shown that activation of several caspases in PBMCs from autistic subjects. The 166

105 cathepsin D protein expression was notably higher in the pyramidal mRNA levels for caspase-1, -2, -4, -5 were also found to be sig- 167

106 and granule cells of the hippocampus, in the neurons of the cere- nificantly increased in autistic children as compared to healthy 168

107 bellum, and in the frontal cortices of autistic subjects as compared subjects. In addition, protein levels of caspase-3, -7, -12 were shown 169

108 with the age-matched control subjects (Sheikh et al., 2010a). And to be increased in autistic patients (Siniscalco et al., 2012). How- 170

109 cathepsin D mRNA and protein expression were also significantly ever, the findings in the peripheral blood of autistic patients may 171

110 increased in autistic lymphoblasts (Malik et al., 2011). not correlate with that in the central nervous system. 172

111 Several studies have shown that cathepsin D may be involved Propionic acid has often been reported to induce a number 173

112 in inflammation. Fusek et al. (2007) reported that procathepsin of behavioral changes, neuroinflammation responses and oxida- 174

113 D initiated secretion of cytokines. Erdmann et al. (2008) found tive stress similar to those observed in humans with autism 175

114 that inflammatory cytokines, including TNF-␣ and IFN-␥, increased (MacFabe et al., 2008). It was showed that the level of caspase- 176

115 extracellular procathepsin D in primary endothelial cell cultures. 3 was elevated in propionic acid-treated rat and the elevation of 177

116 Recently, several studies have demonstrated that several inflam- caspase-3 proved the pro-apoptotic and neurotoxic effect of pro- 178

117 matory cytokines such as TGF-␤1, MCP-1, IL-6, IL-8, IL-10, GM-CSF, pionic acid to rat pups (El-Ansary et al., 2012). A similar increase 179

118 TNF-␣ and IFN-␥ were increased in autistic brains and lym- in caspase-3 has been reported in developing rat brains as neuro- 180

119 phoblasts (Li et al., 2009; Malik et al., 2011; Vargas et al., 2005). In toxic effects of thimerosal, an environmental factor involved in the 181

120 addition, studies have also demonstrated that apoptosis can be ini- etiology of autism (Olczak et al., 2010). In addition, sodium val- 182

121 tiated by activation of a group of inflammatory cytokines (Grunnet proate administered to neonatal mice causes cognitive and motor 183

122 et al., 2009; Wright et al., 1999), and cathepsin D protease medi- deficits similar to those observed in humans with autism. The num- 184

123 ates apoptosis induced by cytokines TNF-␣ and IFN-␥ (Deiss et al., ber of TUNEL-positive cells was significantly increased in sodium 185

Please cite this article in press as: Wei, H., et al., The apoptotic perspective of autism. Int. J. Dev. Neurosci. (2014),
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186 valproate-treated mice in the external granule cell layer of the 3.2. Ras/Raf/ERK1/2 signaling pathway 248

187 cerebellum and dentate gyrus of the hippocampus (Yochum et al.,

188 2008). These observations provided a histopathological findings of The Ras/Raf/ERK1/2 signaling pathway belongs to the family 249

189 apoptosis in autism. of mitogen-activated protein kinases (MAPK). Ras protein can be 250

activated in response to extracellular stimuli and controls various 251

cell responses, such as cell proliferation, migration, differentiation 252

190 3. Apoptosis-related signaling pathway in autism and apoptotic cell death (Murphy and Blenis, 2006). In the nervous 253

system, Ras/Raf/ERK signaling has been shown to play important 254

191 3.1. BDNF-Akt-Bcl2 signaling pathway roles in the genesis of neural progenitors, learning, and memory 255

(Davis and Laroche, 2006). On the other hand, a number of stud- 256

192 Akt has been implicated as an anti-apoptotic protein in many ies have demonstrated a death-promoting role for ERK1/2 in both 257

193 different cell death paradigms (Franke et al., 2003). The Akt path- in vitro and in vivo models of neuronal death. ERK5 has also been 258

194 ways are important intracellular signaling systems used by growth identified and implicated in neuronal apoptotic death (Cavanaugh, 259

195 factors involved in the survival and maintenance of many neu- 2004). It has been demonstrated a possible association between 260

196 ral cell populations (Frebel and Wiese, 2006; Zheng and Quirion, neural cell death and autism. Studies have reported that many 261

197 2004) and implicated in the pathology of autism (Chen et al., 2014). areas of the brain exhibit abnormalities in autism, including loss 262

198 Sheikh et al. (2010b) found that the expression and phosphoryla- of pyramidal neurons and granule cells in the hippocampus as well 263

199 tion/activation of Akt kinase that regulates Bcl-2 are significantly as significant loss and atrophy of Purkinje cells in the cerebellum 264

200 decreased in the autistic brain. Brain-derived neurotrophic factor (Bauman and Kemper, 1985; Ritvo et al., 1986). In addition, a dele- 265

201 (BDNF) is known to bind with high-affinity to the TrkB receptor, tion of a locus on chromosome 16, which included the MAPK3 266

202 which leads to the activation of the phosphoinositide 3-kinase gene that encodes ERK1, is associated with autism (Weiss et al., 267

203 (PI3K)/Akt/Bcl2 pathway (Huang and Reichardt, 2003). Activation 2008). Recently, Ras/Raf/ERK1/2 signaling was found to be up- 268

204 of these pathways promotes neuronal survival and differentiation regulated in BTBR mice, which is currently used as a mouse model 269

205 and regulates synaptic transmission in the peripheral and cen- to study autism, relative to matched control B6 mice (Yin et al., 270

206 tral nervous systems (Bibel and Barde, 2000). Consistently, BDNF 2014). Interestingly, the developmental pattern of Ras/Raf/ERK1/2 271

207 was significantly decreased in the cerebral cortex of autistic sub- signaling was up-regulated in newborn and 2-week old BTBR mice 272

208 jects in comparison with the age-matched controls (Sheikh et al., but unaltered in 3-week and 6-week old samples. The author 273

209 2010b). Although it has been showed that higher BDNF levels in stated that the alteration of Ras/Raf/ERK signaling in the early 274

210 archived samples of neonatal blood and serum obtained from autis- developmental stages in mice could contribute to the noted autis- 275

211 tic subjects in comparison with normal controls (Miyazaki et al., tic phenotype. With an adenoviral gene delivery approach, the 276

212 2004; Nelson et al., 2001). However, lately, from a careful and researcher developed a mouse model, Ad-green fluorescent pro- 277

213 large-sample study, another group reported that the mean levels tein (GFP)-Raf mice, with enhanced Raf/Erk1/2 signaling in the 278

214 of BDNF were significantly lower in the serum of autistic children brain. This pilot studies showed that Ad-GFP-Raf mice produced 279

215 0–9 years old compared with teenagers or adults or with age- certain autistic features, including repetitive behavior, decreased 280

216 matched healthy controls (Katoh-Semba et al., 2007). Although the social interactions, impaired cognitive abilities, and increased anx- 281

217 level of BDNF in the brain does not necessarily correlate with that iety, as compared with the control mice. Furthermore, in cultured 282

218 in the serum, the finding that BDNF is significantly decreased in cortical neural cells, c-Raf overexpression caused the alteration of 283

219 the brain of autistic subjects is consistent with the study from the cell migration, delay in dendritic spine development, and impair- 284

220 Katoh-Semba group. The decrease of BDNF together with compro- ment in total and excitatory synapse formation (Yang et al., 2013). 285

221 mised Akt activities and Bcl2 expression strongly suggests that the Taking together, these results suggest that the up-regulation of the 286

222 BDNF/Akt/Bcl2 pathway is deregulated in autistic brains, and this Ras/Raf/ERK signaling pathway may contribute to the pathogenesis 287

223 change could be the underlying mechanism that contributes to the of autism through its impairment on cortical neuron development, 288

224 pathogenic change in the autistic brain. which leads to neural circuit imbalances. 289

225 The phosphatase and tensin homolog (PTEN) is a lipid phos- The MET is a receptor tyrosine kinase that, after binding with 290

226 phatase best known for its role in suppressing tumor formation its ligand, hepatocyte growth factor, activates a wide range of 291

227 by inhibiting cellular survival, proliferation, and cellular archi- different cellular signaling pathways, including those involved in 292

228 tecture (Song et al., 2012). However, individuals that harbor cell growth, survival and migration (Organ and Tsao, 2011). MET 293

229 PTEN inactivating germline mutations are also prone to develop expression has also been observed in various structures of the 294

230 neurological disorders, including macrocephaly, epilepsy, mental embryonic and postnatal nervous system, including spinal cord 295

231 retardation/developmental delay and autism (Zhou and Parada, motor neurons, migrating neural crest cells and sensory neurons 296

232 2012). PTEN mutations are present in 5–10% of people with autism, (Andermarcher et al., 1996; Jung et al., 1994; Maina et al., 1997; 297

233 loss-of-function point mutations in this gene give rise to pro- Sonnenberg et al., 1993). MET have been implicated in syndromic 298

234 gressive macrocephaly, a hallmark feature that occurs in nearly and idiopathic causes of autism (Levitt and Campbell, 2009; Rudie 299

235 20% of humans with autism (Takeuchi et al., 2013). In addition et al., 2012). MET protein levels in postmortem temporal cortex 300

236 to anatomical abnormalities, individuals with inactivating PTEN were significantly decreased in autism cases compared with con- 301

237 mutations exhibit spontaneous seizures and deficits in social and trol subjects (Campbell et al., 2007). Different studies suggest that 302

238 cognitive behaviors. Although the specific mechanism that PTEN MET triggers either anti-apoptotic or pro-apoptotic signals and the 303

239 mutation causes anatomical abnormalities behavioral defects in mechanisms by which MET exerts these opposite effects are not 304

240 autism is unknown, one possibility is that PTEN involves in the fully understood. The contrary actions of MET may be dependent on 305

241 regulation of apoptosis by antagonizing the PI3K/Akt signaling both the cell context and the expression of coreceptors and down- 306

242 pathway (Kyrylenko et al., 1999; Zhu et al., 2006). The findings stream pro- or anti-apoptotic effectors involved in MET signaling 307

243 indicate that the down-regulation of the important BDNF-Akt- (Trusolino et al., 2010; Tulasne et al., 2004; Xiao et al., 2001). The 308

244 Bcl-2 signaling pathway may be one of the key causes of autism. downstream signal transduction pathways include MAPK cascades, 309

245 Future studies should extend and confirm these findings in other PI3K/Akt axis and signal transducer and activator of transcription 310

246 regions of the brain and with a greater quantity of postmortem proteins (Trusolino et al., 2010). However, either anti-apoptotic or 311

247 brains. pro-apoptotic role of MET signaling in the pathology of autism still 312

Please cite this article in press as: Wei, H., et al., The apoptotic perspective of autism. Int. J. Dev. Neurosci. (2014),
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313 needs to be further investigated. Furthermore, links between these cytochrome c (Zhang and Bhavnani, 2006). Recently, serum neu- 345

314 autism-related signaling pathways are also unclear. rotensin levels have been found to be higher in autistic children 346

than those of normal children (Angelidou et al., 2010). Neurotensin 347

315 4. Oxidative stress and glutamate excitotoxicity is known to intensify neuronal N-methyl-d-aspartate-mediated 348

glutamate signaling. Thus, Ghanizadeh postulated that neurotensin 349

316 The oxidative state plays a key role in the regulation and con- may accentuate the hyperglutaminergic state in autism and tar- 350

317 trol of the cell survival and cell death through its interaction with geting neurotensin might be a possible novel approach for the 351

318 cellular macromolecules and signal transduction pathway (Buttke treatment of autism (Ghanizadeh, 2010). 352

319 and Sandstrom, 1994; Loh et al., 2006). It was known that oxidative
320 stress could act as a mediator of neuronal apoptosis in neuropsychi- 5. Conclusion 353

321 atric disorder, such as Alzheimer’s disease and schizophrenia (Loh

322 et al., 2006; Mahadik et al., 2001). It is worth noting that the human data presented in this review 354

323 Recent evidence points toward an association between oxida- was largely from childhood and adolescence. As the theory of 355

324 tive stress and autism (Pardo and Eberhart, 2007). Oxidative stress age-specific anatomic abnormalities in autism states, early brain 356

325 in autism has been studied at the membrane level and also by overgrowth during infancy and the toddler years, followed by 357

326 measuring products of lipid peroxidation, detoxifying agents, and an accelerated rate of decline in size and perhaps degeneration 358

327 antioxidants involved in the defense system against reactive oxy- from adolescence to late middle age in autism (Courchesne et al., 359

328 gen species. In brief, existing evidences demonstrated increased 2011a,b). In addition, it was reported that apoptosis was impaired 360

329 oxidative stress in autism and it has been suggested that oxida- and resulted in abnormal retention of developmentally transient 361

330 tive stress is another possible cause of Purkinje cell loss and other neurons in the developing brain of fragile X mental retardation 362

331 neuroanatomical changes described in autistic brains (Pardo and protein-deficient mice (Cheng et al., 2013; Gatto and Broadie, 363

332 Eberhart, 2007). 2011). It may contribute to excess and aberrant neurons and early 364

333 Glutamate and gamma-aminobutyric acid (GABA) are the main brain volume overgrowth in autism. Based on the existing findings, 365

334 excitatory and inhibitory neurotransmitters in the human brain it seems that there is an age-related apoptotic changes, deficient 366

335 and both have important roles during early brain development. apoptosis in the developing infant brain and excessive apoptosis in 367

336 Cumulative evidence indicates that dysfunctional excitatory and the childhood and adolescence autistic brain. The rapid overgrowth 368

337 inhibitory synaptic activities could be the underlying mechanism prevents the brains of children with autism from forming functional 369

338 responsible for the development of autism. In addition, a number connections, and may underlie the early emergence of behavioral 370

339 of studies have reported imbalance in glutamate-to-GABA ratios deficits. Enhanced apoptosis could further affect the normal brain 371

340 in children with autism. It was shown higher levels of glutamate maturation and aggravate autism symptoms. 372

341 and decreased GABA(A) receptors in autism (Harada et al., 2011; Taken together, a possible working mechanism of apoptosis 373

342 Shinohe et al., 2006; Fatemi et al., 2009). Glutamate causes neuronal involved in the pathogenesis of autism is speculated and sum- 374

343 apoptosis at high concentrations and was associated with regula- marized in Fig. 1. The genetic change, environment, oxidative 375

344 tion of genes such as Bcl-2, Bax, and/or caspase-3 and mitochondrial stress and glutamate excitotoxicity caused either a reduction of 376

anti-apoptotic proteins or increased expression of pro-apoptotic 377

proteins, regulated via the apoptosis-related signaling pathways 378

such as Akt-Bcl-2, Ras/Raf/ERK1/2 and MET signaling pathways. 379

The activation of pathological apoptosis impaired normal brain 380

maturation and mediated autism-like behaviors. However, it is con- 381

ceivable that many fundamental questions remain to be answered. 382

Future studies of pro- and anti-apoptotic proteins may provide 383

new insights into prevention and treatment of autism and other 384

neurodevelopmental disorders. 385

Acknowledgements 386

This work was supported by grants to H. Wei from the National Q2 387

Natural Science Foundation of China (No. 81201061), Shanxi 388

Scholarship Council of China (No. 2013-124) and Natural Science 389

Foundation of Shanxi (No. 2013021036-2). 390

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