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2 Neurogenesis in the amygdala: A new etiologic

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3 hypothesis of autism?

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4 Marcos Tomanik Mercadante a,*, Roberta Monterazzo Cysneiros b,
5 José Salomão Schwartzman c, Ricardo Mario Arida d,
6 Esper Abrão Cavalheiro e, Fulvio Alexandre Scorza e

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a
7 Department of Psychiatry, Universidade Federal de São Paulo/Escola Paulista de Medicina
8 (UNIFESP/EPM), Rua Botucatu 740 – 3° andar, ZIP 04023-900 São Paulo, Brazil
b
9 Department of Pharmacology, Centro Universitário São Camilo, São Paulo, Brazil
10
11
12
c
d
D
Pervasive Developmental Disorders Program, Universidade Presbiteriana Mackenzie, São Paulo, Brazil
Department of Physiology, Universidade Federal de São Paulo/Escola Paulista de Medicina
(UNIFESP/EPM), São Paulo, Brazil
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e
13 Experimental Neurology, Universidade Federal de São Paulo/Escola Paulista de Medicina
14 (UNIFESP/EPM), São Paulo, Brazil

Received 6 May 2007; accepted 9 May 2007

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Summary Neurogenesis studies had an increased development after BrdU (5-bromo-30 -deoxyuridine), a marker of cell
proliferation. Today, several studies have showed the relevance of neurogenesis in the hippocampal formation.
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Notwithstanding, other brains areas have been described presenting neurogenesis, including the amygdala. This key
structure is a complex cerebral region which has been associated with social behaviors and the emotional significance
of the daily experiences. Several studies have associated the amygdala to the autism, a severe neurodevelopmental
disorder. In this paper, we discuss the hypothesis of neurogenesis in the amygdala as a contributing cause of autism.
The social skills require competent new neuronal connections, including efficient plasticity synaptic rearranging.
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Interestingly, emotional context cannot be imprinting in mature neurons in the presence of GABA, a neurotransmitter
release during new environments experiences. However, it is known that new neurons are not well responsive to GABA
stimulation, allowing the long-term potentiation necessary for the learning process. Based on these evidence it is
tantalizing to hypothesize that the sociability impairment seen in some individuals with autism may partly be assigned
to impaired regulation of the GABAergic system and to the impact of this impairment on the adequate functioning of
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the amygdala and on its capacity to store new experiences and to modulate the plasticity of the corticostriatal
connections.
c 2007 Published by Elsevier Ltd.

32

Neurogenesis: general aspects 33

* Corresponding author. Tel.: +55 11 5579 2828.
E-mail address: mt.mercadante@uol.com.br (M.T. Merca- In the end of the 19th and beginning of 20th centu- 34
dante). ries, Koelliker [2] and His [3] studied the develop- 35


0306-9877/$ - see front matter c 2007 Published by Elsevier Ltd.
doi:10.1016/j.mehy.2007.05.018

Please cite this article in press as: Mercadante MT, et al., Neurogenesis in the amygdala: A new etiologic hypothesis of
autism?, Med Hypotheses (2007), doi:10.1016/j.mehy.2007.05.018
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2 Mercadante et al.

36 ment of the central nervous system (CNS) in human phase, are located in specific regions [19,20]. 92
37 beings and other mammalians, and found that the These regions are the ventricles, specifically the 93
38 cerebral structure remained fixed after birth. Soon subventricular zone of the lateral ventricles (SVZ) 94
39 afterwards, Ramón y Cajal [4] described that, ‘‘in and the hippocampal formation, specifically the 95
40 the adult centers, the nerve paths are something subgranular zone of the dentate gyrus (SGZ) at 96
41 fixed and immutable: everything may die, nothing the point where the internal layer of granule cells 97
42 may be regenerated. It is for the science of the fu- of the dentate gyrus meets the hilus. In the SVZ, 98
43 ture to change, if possible, this harsh decree’’. 30,000 new cells are generated bilaterally per day 99
44 However, in the first half of the 20tth Century, in adult mice [21]. These cells migrate towards 100
45 some authors suggested the existence of a cerebral the olfactory bulb along a well-defined pathway, 101

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46 mitotic process in rats after birth [5–7], but did called the rostral migratory stream (RMS), a pro- 102
47 not clearly identify whether such dividing cells be- cess that takes about 2–6 days [21–23]. After 103

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48 came neuronal or glial cells. reaching the olfactory bulb, these cells migrate 104
49 Studies about neurogenesis advanced after the radially towards the cell layers, where they differ- 105
50 development of the autoradiography technique entiate into a large variety of cell types, such as 106
51 with [3H]-thymidine, which is incorporated into periglomerular neurons and interneurons, as well 107
52 the DNA of proliferating cells. Joseph Altman used as astrocytes and oligodendrocytes [21] (Fig. 1). 108
this technique and demonstrated the occurrence of Although it is unknown why the olfactory bulb

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53 109
54 neurogenesis in several cerebral structures of needs such a considerable number of new cells, it 110
55 young and adult rats, such as in the dentate gyrus is easier to speculate the reason why the hippocam- 111
56 [8], neocortex [9], and olfactory bulb [10]. Altman pal formation needs them: This encephalic region is 112
57 argued that those new neurons were ‘‘microneu- crucial for the acquisition and retention of new 113
58 rons’’ – granule or stellate cells with short axons information. Therefore, the greater the number of 114

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59 – and suggested that they played a role in learning cells, the more efficient the cognitive processes 115
60 and memory processes. Techniques available at will be. Studies that investigated neurogenesis in 116
61 that time were incapable of accurately demon- the hippocampal formation showed that, of the 117
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62 strating whether those cells were neurons or glial principal neuron populations in this region, the 118
63 cells, and, therefore, Altman results were ignored. granule cells of the dentate gyrus are the ones that 119
64 However, after the development of electronic retain a mitotic capacity postnatal [8,18]. Most 120
65 microscopy, Kaplan showed that the cells in the granule cells of the dentate gyrus are generated in 121
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66 dentate gyrus and olfactory bulb of adult rats that the postnatal period. However, the full develop- 122
67 incorporated [3H]-thymidine had ultrastructural ment of the granule cell layer occurs between the 123
68 characteristics of neurons [11]. 20th and 25th days of life. Granule cells are origi- 124
69 Finally, significant advances in the study of neu- nated from progenitor cells located in the hilus of 125
rogenesis occurred in the 1990s, with the develop- the dentate gyrus. They are initially spread all over
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70 126
71 ment of the synthetic analog of thymidine, BrdU the hilus, and, in the second postnatal week, they 127
72 (5-bromo-30 -deoxyuridine). BrdU is incorporated are found in the SGZ of the dentate gyrus, where 128
73 into cells in the cell synthesis phase (mitosis S they remain mitotically active. In most organisms, 129
74 phase) and is, therefore, a marker of cell prolifera- this process may persist for substantially long peri- 130
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75 tion. Cell nuclei marked with BrdU may be visual-

76 ized using immunohistochemical techniques,
77 which does not require the use of autoradiography
78 [12].
79 In most of the CNS regions in mammalians, the
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80 appearance of new neurons is a process limited to

81 embryogenesis [13], and once development is com-
82 plete, progenitor cells that originated from neu-
83 rons go through a differentiation process and
84 become incapable of division. However, the neuro-
85 genesis process in the CNS of adults has been de-
86 scribed in several species, such as crustaceans
87 [14], reptiles [15], amphibians [16], birds [17], ro-
Figure 1 Sagittal view shows neurogenesis sites in the
88 dents [8], primates [18] and human beings [19]. In olfactory bulb-subventricular zone system. Cells prolif-
89 all the mammalian species already studied, includ- erate in the subventricular zone and migrate along the
90 ing humans, the mitotically active progenitor cells, rostral migratory stream to the olfactory bulb, where
91 capable of generating new neurons in the adult they differentiate. Adapted by permission of [1].

Please cite this article in press as: Mercadante MT, et al., Neurogenesis in the amygdala: A new etiologic hypothesis of
autism?, Med Hypotheses (2007), doi:10.1016/j.mehy.2007.05.018
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Figure 2 Frontal view of rodent brain shows sites of neurogenesis in the dentate gyrus (DG) in the hippocampal

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formation. Cells proliferate in the subgranular layer (SGL) located in the interface between the granular layer (GL) and
the hilus, where they migrate and differentiate into mature neurons. Adapted by permission of [1].

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131 ods, maybe until senescence [24]. For example, in Studies using animal models suggest that the 171
132 adult rats and monkeys, the progenitor cells are amygdala is an important station in the pathway 172
133 found in the SGZ of the dentate gyrus; in rats, of information responsible for social recognition 173
134 9000 new cells are generated by day [25], whereas processes [34]. The incapacity to store knowledge 174
this number is 200 in monkeys [23]. These new cells of meetings with co-specifics in the memory deter-

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135 175
136 proliferate and migrate continuously into the gran- mines an important impairment in the capacity of 176
137 ule cell layer [26]. In this region, they develop a regulating social interactions. Along the phyloge- 177
138 morphology that is typical of granule cells [27], ex- netic development, recognition mediated by the 178
139 press neuronal differentiation markers [26], and ex- olfactory system, through the pheromonal recogni- 179
140 tend their axons to the pathway of mossy fibers, tion found in mammalians, became primarily man- 180
141
142
143
which project into the CA3 region of the hippocam-
pus [28]. This process of integration into an already
existing circuitry lasts about 4–8 weeks [29]
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aged by the visual and hearing systems in primates.
In human beings, the improvement of this ability
required the specialization of certain regions, such
181
182
183
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144 (Fig. 2). as the fusiform gyrus, the amygdala, and the supe- 184
rior temporal sulcus. Studies that focused on these 185
areas, which are activated in human face and voice 186
145 Neurogenesis in the amygdala: a new recognition tasks, show that these regions, though 187
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146 etiologic hypothesis for autism? activated in normal controls, are not activated in 188
patients with autism [35,36]. 189
147 Autism is a pervasive developmental disorder The development of more sophisticate and accu- 190
148 characterized by impairment of social interac- rate functional cerebral imaging techniques, such 191
as proton emission tomography (PET), single-pho-
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149 tion, verbal and nonverbal communication, re- 192

150 stricted activities and interests, and stereotyped ton emission tomography (SPCT) and functional 193
151 behavioral patterns [30,31]. The causes of autism magnetic resonance (fMRI), have opened the way 194
152 are still unknown, and the neuropathologic pro- to new and promising investigations of cerebral 195
153 cesses associated with it are not well-defined. dysfunction in autism [31]. However, the evalua- 196
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154 Because of the complexity of symptoms of indi- tion of the structure of the amygdala using these 197
155 viduals with autism, it is believed that several techniques yielded controversial results. Howard 198
156 of their cerebral regions have morphofunctional and colleagues (2000) used quantitative MRI and 199
157 changes, which justify the phenotypic diversity found an increase in the volume of the amygdala 200
158 among patients. Of the different cerebral regions in patients with autism. Their data were confirmed 201
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159 that have been associated with autism, the amyg- two years later by Sparks and colleagues [37], who 202
160 dala has been the focus of a large number of also found an increase in the volume of the amyg- 203
161 studies [32]. The amygdala, one of the key struc- dala in 45 children with autism, in a study using 204
162 tures of the limbic system, is a heterogeneous re- three-dimensional MRI. However, Aylward and col- 205
163 gion formed by several nuclear sub regions, leagues (1999) found a reduction in the volume of 206
164 including the basolateral and the corticomedial the amygdala in 14 teenagers with autism in an 207
165 regions, which have different connections and MRI study. A recent study conducted by researchers 208
166 structural characteristics. The amygdalar complex in the Department of Psychiatry of the University of 209
167 seems to play a central role in emotional, moti- California used postmortem stereological measure- 210
168 vational and social processes, and is crucial to as- ments and showed a decrease in the number of 211
169 sign emotional significance to everyday neurons in the amygdala of 9 teenagers and adults 212
170 experiences [33]. with autism [38]. 213

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214 Despite some gaps in knowledge, it may be sug- served in mature granule neurons, an effect that 270
215 gested that the amygdala shows structural changes may be reverted by the action of GABAergic block- 271
216 in association with autism [39]. This region plays an ers. However, young neurons are not inhibited by 272
217 important role in learning and memory, particu- GABA, which may justify the recruitment of this 273
218 larly of the repertoire necessary for the adequate type of cell for learning experiences in new envi- 274
219 establishment of social skills [40]. Learning and ronments when the level of GABA is increased [48]. 275
220 memory take place by the formation of new neural Therefore, the following scenarios may be con- 276
221 connections, and require a plastic capacity to rear- sidered: (1) the amygdala decisively contributes 277
222 range information [41]. Such plasticity is even to the establishment of learning tasks associated 278
223 more demanded in the formation of neuronal cir- with emotional meaning, (2) this learning takes 279

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224 cuits that enable social behaviors because it is nec- place primarily by recruiting new neurons and (3) 280
225 essary to group dozens of different stimuli (each these neurons are less sensitive to decreases in 281

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226 with its neuronal network) to construct the social the GABA-induced activation. 282
227 memory and its accompanying affective and tem- The amygdala has two different embryonic ori- 283
228 poral meanings, for example. gins that form two portions, a cortical and a striate 284
229 Therefore, neurogenesis and neuronal plasticity one [49]. These portions are formed by different 285
230 may have an important role in the dynamics of so- nuclei, which seem to act in different ways. For 286
cial functioning, and the morphologic and func- example, a number of studies demonstrated that

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231 287
232 tional changes found in the amygdalar structure the medial portion of the amygdala is an important 288
233 seem to reflect the unbalance of these processes. site in the circuit responsible for social recognition 289
234 Before we explore the hypothesis of impairment memory [50]. The nucleus located in the striate 290
235 in neuronal plasticity, morphologic changes in the portion of the amygdala seems to be responsible 291
236 amygdala and social impairment, we should go for a primitive function necessary for the establish- 292

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237 back to the formation of new neurons in adult ner- ment of social groups among mammalians. This 293
238 vous tissues. Two specific encephalic regions (SVZ, simply memory is relevant among other, to regu- 294
239 SGZ) are reported to be capable of generating new late the hierarchical behaviors. At the same time, 295
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240 neurons in adult life [19,20]. However, other cere- the basolateral nucleus of the amygdala, located 296
241 bral structures, such as the amygdala, have also in the cortical portion, plays a role in contextual 297
242 been associated with neurogenesis in the adult ner- memory and is relevant to imprint the meaning of 298
243 vous system [1,42,43]. It becomes opportun to ex- the experiences learned [51]. 299
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244 plore the association between neurogenesis in the In sum: in the amygdala, the ability to acquire 300
245 amygdale [43,44] and the morphofunctional meaning from new experiences is modulated by 301
246 changes of this structure in understanding the dys- GABA and requires non-mature neurons. It is inter- 302
247 functional aspects found in the development of esting to note that individuals with autism have 303
sociability in children with autism. How this associ- important changes in the GABAergic system [52].
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248 304
249 ation takes place is a challenge for future investi- The decrease of this neurotransmitter seems to 305
250 gations. Some studies showed an increase in the have an effect on cerebral organization, which re- 306
251 volume of the amygdala, and suggested either an sults, for example, in changes in neuronal migra- 307
252 increase in neurogenesis or a decrease in neuronal tion [53] and organization of GABAergic 308
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253 pruning [45]. At the same time, other studies re- interneuron’s, and which compromises the inhibi- 309
254 ported a decrease in the volume of the amygdala tory system in these patients [54]. 310
255 [46], which reinforces the idea that the neuronal We may, therefore, hypothesize that the socia- 311
256 plasticity of people with autism is affected in the bility impairment seen in some individuals with 312
257 amygdalar region. autism may partly be assigned to impaired regula- 313
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258 What impact, therefore, would such changes tion of the GABAergic system and to the impact 314
259 have on neuronal plasticity of the amygdala and of this impairment on the adequate functioning of 315
260 on the social performance of an individual? Evi- the amygdala and on its capacity to store new 316
261 dence shows that new neurons have a more rele- experiences [47,48] and to modulate the plasticity 317
262 vant role in learning tasks that have a greater of the corticostriatal connections [55]. The de- 318
263 emotional content, tasks that require the activa- crease in neurons found in a postmortem study con- 319
264 tion of the hippocampus and the amygdala, differ- firms this hypothesis [38]. 320
265 ently from the pattern found in tasks of visual and Recent studies have demonstrated that neuro- 321
266 spatial learning, which do not require the activa- genesis in the CNS of adults is markedly affected 322
267 tion of the amygdala [47]. Interestingly, in the by a large number of stimuli. Therefore, strategies 323
268 presence of GABAergic stimulation, there is a de- may be adopted to improve the mitotic process in 324
269 crease in long-term potentiation particularly ob- the amygdalar complex of people with autism. 325

Please cite this article in press as: Mercadante MT, et al., Neurogenesis in the amygdala: A new etiologic hypothesis of
autism?, Med Hypotheses (2007), doi:10.1016/j.mehy.2007.05.018
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Please cite this article in press as: Mercadante MT, et al., Neurogenesis in the amygdala: A new etiologic hypothesis of
autism?, Med Hypotheses (2007), doi:10.1016/j.mehy.2007.05.018