- Email: [email protected]
Neurogenesis in the amygdala: A new etiologic hypothesis of autism?
Medical Hypotheses (2008) 70, 352–357
http://intl.elsevierhealth.com/journals/mehy
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? Marcos Tomanik Mercadante a,*, Roberta Monterazzo Cysneiros b, ˜o Schwartzman c, Ricardo Mario Arida d, ´ Saloma Jose ˜o Cavalheiro e, Fulvio Alexandre Scorza e Esper Abra a
˜o Paulo/Escola Paulista de Medicina Department of Psychiatry, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Rua Botucatu 740 – 3° andar, ZIP 04023-900 Sa b ´rio Sa ˜o Camilo, Sa ˜o Paulo, Brazil Department of Pharmacology, Centro Universita c ˜o Paulo, Brazil Pervasive Developmental Disorders Program, Universidade Presbiteriana Mackenzie, Sa d ˜o Paulo/Escola Paulista de Medicina Department of Physiology, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Sa e ˜o Paulo/Escola Paulista de Medicina Experimental Neurology, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Sa Received 6 May 2007; accepted 9 May 2007
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. 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. 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 the amygdala and on its capacity to store new experiences and to modulate the plasticity of the corticostriatal connections. c 2007 Elsevier Ltd. All rights reserved.
Neurogenesis: general aspects * Corresponding author. Tel.: +55 11 5579 2828. E-mail address: [email protected] (M.T. Mercadante).
In the end of the 19th and beginning of 20th centuries, Koelliker [2] and His [3] studied the
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.05.018
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? development of the central nervous system (CNS) in human beings and other mammalians, and found that the cerebral structure remained fixed after birth. Soon afterwards, Ramo ´n y Cajal [4] described that, ‘‘in the adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree’’. However, in the first half of the 20tth Century, some authors suggested the existence of a cerebral mitotic process in rats after birth [5–7], but did not clearly identify whether such dividing cells became neuronal or glial cells. Studies about neurogenesis advanced after the development of the autoradiography technique with [3H]-thymidine, which is incorporated into the DNA of proliferating cells. Joseph Altman used this technique and demonstrated the occurrence of neurogenesis in several cerebral structures of young and adult rats, such as in the dentate gyrus [8], neocortex [9], and olfactory bulb [10]. Altman argued that those new neurons were ‘‘microneurons’’ – granule or stellate cells with short axons – and suggested that they played a role in learning and memory processes. Techniques available at that time were incapable of accurately demonstrating whether those cells were neurons or glial cells, and, therefore, Altman results were ignored. However, after the development of electronic microscopy, Kaplan showed that the cells in the dentate gyrus and olfactory bulb of adult rats that incorporated [3H]-thymidine had ultrastructural characteristics of neurons [11]. Finally, significant advances in the study of neurogenesis occurred in the 1990s, with the development of the synthetic analog of thymidine, BrdU (5-bromo-30 -deoxyuridine). BrdU is incorporated into cells in the cell synthesis phase (mitosis S phase) and is, therefore, a marker of cell proliferation. Cell nuclei marked with BrdU may be visualized using immunohistochemical techniques, which does not require the use of autoradiography [12]. In most of the CNS regions in mammalians, the appearance of new neurons is a process limited to embryogenesis [13], and once development is complete, progenitor cells that originated from neurons go through a differentiation process and become incapable of division. However, the neurogenesis process in the CNS of adults has been described in several species, such as crustaceans [14], reptiles [15], amphibians [16], birds [17], rodents [8], primates [18] and human beings [19]. In all the mammalian species already studied, including humans, the mitotically active progenitor cells, capable of generating new neurons in the adult
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phase, are located in specific regions [19,20]. These regions are the ventricles, specifically the subventricular zone of the lateral ventricles (SVZ) and the hippocampal formation, specifically the subgranular zone of the dentate gyrus (SGZ) at the point where the internal layer of granule cells of the dentate gyrus meets the hilus. In the SVZ, 30,000 new cells are generated bilaterally per day in adult mice [21]. These cells migrate towards the olfactory bulb along a well-defined pathway, called the rostral migratory stream (RMS), a process that takes about 2–6 days [21–23]. After reaching the olfactory bulb, these cells migrate radially towards the cell layers, where they differentiate into a large variety of cell types, such as periglomerular neurons and interneurons, as well as astrocytes and oligodendrocytes [21] (Fig. 1). Although it is unknown why the olfactory bulb needs such a considerable number of new cells, it is easier to speculate the reason why the hippocampal formation needs them: This encephalic region is crucial for the acquisition and retention of new information. Therefore, the greater the number of cells, the more efficient the cognitive processes will be. Studies that investigated neurogenesis in the hippocampal formation showed that, of the principal neuron populations in this region, the granule cells of the dentate gyrus are the ones that retain a mitotic capacity postnatal [8,18]. Most granule cells of the dentate gyrus are generated in the postnatal period. However, the full development of the granule cell layer occurs between the 20th and 25th days of life. Granule cells are originated from progenitor cells located in the hilus of the dentate gyrus. They are initially spread all over the hilus, and, in the second postnatal week, they are found in the SGZ of the dentate gyrus, where they remain mitotically active. In most organisms, this process may persist for substantially long peri-
Figure 1 Sagittal view shows neurogenesis sites in the olfactory bulb-subventricular zone system. Cells proliferate in the subventricular zone and migrate along the rostral migratory stream to the olfactory bulb, where they differentiate. Adapted by permission of [1].
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Mercadante et al.
Figure 2 Frontal view of rodent brain shows sites of neurogenesis in the dentate gyrus (DG) in the hippocampal 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].
ods, maybe until senescence [24]. For example, in adult rats and monkeys, the progenitor cells are found in the SGZ of the dentate gyrus; in rats, 9000 new cells are generated by day [25], whereas this number is 200 in monkeys [23]. These new cells proliferate and migrate continuously into the granule cell layer [26]. In this region, they develop a morphology that is typical of granule cells [27], express neuronal differentiation markers [26], and extend their axons to the pathway of mossy fibers, which project into the CA3 region of the hippocampus [28]. This process of integration into an already existing circuitry lasts about 4–8 weeks [29] (Fig. 2).
Neurogenesis in the amygdala: a new etiologic hypothesis for autism? Autism is a pervasive developmental disorder characterized by impairment of social interaction, verbal and nonverbal communication, restricted activities and interests, and stereotyped behavioral patterns [30,31]. The causes of autism are still unknown, and the neuropathologic processes associated with it are not well-defined. Because of the complexity of symptoms of individuals with autism, it is believed that several of their cerebral regions have morphofunctional changes, which justify the phenotypic diversity among patients. Of the different cerebral regions that have been associated with autism, the amygdala has been the focus of a large number of studies [32]. The amygdala, one of the key structures of the limbic system, is a heterogeneous region formed by several nuclear sub regions, including the basolateral and the corticomedial regions, which have different connections and structural characteristics. The amygdalar complex seems to play a central role in emotional, motivational and social processes, and is crucial to assign emotional significance to everyday experiences [33].
Studies using animal models suggest that the amygdala is an important station in the pathway of information responsible for social recognition processes [34]. The incapacity to store knowledge of meetings with co-specifics in the memory determines an important impairment in the capacity of regulating social interactions. Along the phylogenetic development, recognition mediated by the olfactory system, through the pheromonal recognition found in mammalians, became primarily managed by the visual and hearing systems in primates. In human beings, the improvement of this ability required the specialization of certain regions, such as the fusiform gyrus, the amygdala, and the superior temporal sulcus. Studies that focused on these areas, which are activated in human face and voice recognition tasks, show that these regions, though activated in normal controls, are not activated in patients with autism [35,36]. The development of more sophisticate and accurate functional cerebral imaging techniques, such as proton emission tomography (PET), single-photon emission tomography (SPCT) and functional magnetic resonance (fMRI), have opened the way to new and promising investigations of cerebral dysfunction in autism [31]. However, the evaluation of the structure of the amygdala using these techniques yielded controversial results. Howard and colleagues (2000) used quantitative MRI and found an increase in the volume of the amygdala in patients with autism. Their data were confirmed two years later by Sparks and colleagues [37], who also found an increase in the volume of the amygdala in 45 children with autism, in a study using three-dimensional MRI. However, Aylward and colleagues (1999) found a reduction in the volume of the amygdala in 14 teenagers with autism in an MRI study. A recent study conducted by researchers in the Department of Psychiatry of the University of California used postmortem stereological measurements and showed a decrease in the number of neurons in the amygdala of 9 teenagers and adults with autism [38].
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? Despite some gaps in knowledge, it may be suggested that the amygdala shows structural changes in association with autism [39]. This region plays an important role in learning and memory, particularly of the repertoire necessary for the adequate establishment of social skills [40]. Learning and memory take place by the formation of new neural connections, and require a plastic capacity to rearrange information [41]. Such plasticity is even more demanded in the formation of neuronal circuits that enable social behaviors because it is necessary to group dozens of different stimuli (each with its neuronal network) to construct the social memory and its accompanying affective and temporal meanings, for example. Therefore, neurogenesis and neuronal plasticity may have an important role in the dynamics of social functioning, and the morphologic and functional changes found in the amygdalar structure seem to reflect the unbalance of these processes. Before we explore the hypothesis of impairment in neuronal plasticity, morphologic changes in the amygdala and social impairment, we should go back to the formation of new neurons in adult nervous tissues. Two specific encephalic regions (SVZ, SGZ) are reported to be capable of generating new neurons in adult life [19,20]. However, other cerebral structures, such as the amygdala, have also been associated with neurogenesis in the adult nervous system [1,42,43]. It becomes opportun to explore the association between neurogenesis in the amygdale [43,44] and the morphofunctional changes of this structure in understanding the dysfunctional aspects found in the development of sociability in children with autism. How this association takes place is a challenge for future investigations. Some studies showed an increase in the volume of the amygdala, and suggested either an increase in neurogenesis or a decrease in neuronal pruning [45]. At the same time, other studies reported a decrease in the volume of the amygdala [46], which reinforces the idea that the neuronal plasticity of people with autism is affected in the amygdalar region. What impact, therefore, would such changes have on neuronal plasticity of the amygdala and on the social performance of an individual? Evidence shows that new neurons have a more relevant role in learning tasks that have a greater emotional content, tasks that require the activation of the hippocampus and the amygdala, differently from the pattern found in tasks of visual and spatial learning, which do not require the activation of the amygdala [47]. Interestingly, in the presence of GABAergic stimulation, there is a decrease in long-term potentiation particularly ob-
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served in mature granule neurons, an effect that may be reverted by the action of GABAergic blockers. However, young neurons are not inhibited by GABA, which may justify the recruitment of this type of cell for learning experiences in new environments when the level of GABA is increased [48]. Therefore, the following scenarios may be considered: (1) the amygdala decisively contributes to the establishment of learning tasks associated with emotional meaning, (2) this learning takes place primarily by recruiting new neurons and (3) these neurons are less sensitive to decreases in the GABA-induced activation. The amygdala has two different embryonic origins that form two portions, a cortical and a striate one [49]. These portions are formed by different nuclei, which seem to act in different ways. For example, a number of studies demonstrated that the medial portion of the amygdala is an important site in the circuit responsible for social recognition memory [50]. The nucleus located in the striate portion of the amygdala seems to be responsible for a primitive function necessary for the establishment of social groups among mammalians. This simply memory is relevant among other, to regulate the hierarchical behaviors. At the same time, the basolateral nucleus of the amygdala, located in the cortical portion, plays a role in contextual memory and is relevant to imprint the meaning of the experiences learned [51]. In sum: in the amygdala, the ability to acquire meaning from new experiences is modulated by GABA and requires non-mature neurons. It is interesting to note that individuals with autism have important changes in the GABAergic system [52]. The decrease of this neurotransmitter seems to have an effect on cerebral organization, which results, for example, in changes in neuronal migration [53] and organization of GABAergic interneuron’s, and which compromises the inhibitory system in these patients [54]. We may, therefore, 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 the amygdala and on its capacity to store new experiences [47,48] and to modulate the plasticity of the corticostriatal connections [55]. The decrease in neurons found in a postmortem study confirms this hypothesis [38]. Recent studies have demonstrated that neurogenesis in the CNS of adults is markedly affected by a large number of stimuli. Therefore, strategies may be adopted to improve the mitotic process in the amygdalar complex of people with autism.
356 One of these strategies would be physical activity. Henriette van Praag and colleagues [56] showed that physical activity increases cell proliferation, survival and neurogenesis in the hippocampal formation of mice. These data suggest one more beneficial effect of the daily practice of physical activity, and may explain why individuals that practice exercises regularly have a better cognitive performance. One of the interventions proposed for individuals with autism is a method based on a physical activity program, the Higashi method [57]. However, no clinical trials have shown the advantages of this methods over others currently used. Moreover, it seems to be clear that not all demands observed in people with autism may be met by using this method. However, it is possible that some of the impairment found in a subgroup of people with autism may be reversed by an increase in neurogenesis and plasticity in certain cerebral regions.
Conclusion The hypotheses that were discussed in this paper suggest that neurogenesis may be involved in the physiopathology of autism. Therefore, interventions to increase neurogenesis may become one more therapeutic alternative for this pervasive developmental disorder. Undoubtedly, although this model may explain processes in some individuals with autism, it is not sufficient to understand all the signs and symptoms observed in these cases or all the possible subgroups of individuals with autism. However, neurogenesis may be a new paradigm for the understanding of part of the biological processes associated with autism. As most of our suggestions are still speculative, studies with animals should be conducted to investigate the neurogenesis-autism hypothesis. Moreover, we suggest that this hypothesis be evaluated using specific markers for cell proliferation, migration and differentiation in necropsy encephalic tissues of patients with autism. If confirmed, this hypothesis may lead to the formulation of new therapeutic approaches to autism.
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http://intl.elsevierhealth.com/journals/mehy
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? Marcos Tomanik Mercadante a,*, Roberta Monterazzo Cysneiros b, ˜o Schwartzman c, Ricardo Mario Arida d, ´ Saloma Jose ˜o Cavalheiro e, Fulvio Alexandre Scorza e Esper Abra a
˜o Paulo/Escola Paulista de Medicina Department of Psychiatry, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Rua Botucatu 740 – 3° andar, ZIP 04023-900 Sa b ´rio Sa ˜o Camilo, Sa ˜o Paulo, Brazil Department of Pharmacology, Centro Universita c ˜o Paulo, Brazil Pervasive Developmental Disorders Program, Universidade Presbiteriana Mackenzie, Sa d ˜o Paulo/Escola Paulista de Medicina Department of Physiology, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Sa e ˜o Paulo/Escola Paulista de Medicina Experimental Neurology, Universidade Federal de Sa ˜o Paulo, Brazil (UNIFESP/EPM), Sa Received 6 May 2007; accepted 9 May 2007
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. 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. 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 the amygdala and on its capacity to store new experiences and to modulate the plasticity of the corticostriatal connections. c 2007 Elsevier Ltd. All rights reserved.
Neurogenesis: general aspects * Corresponding author. Tel.: +55 11 5579 2828. E-mail address: [email protected] (M.T. Mercadante).
In the end of the 19th and beginning of 20th centuries, Koelliker [2] and His [3] studied the
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.05.018
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? development of the central nervous system (CNS) in human beings and other mammalians, and found that the cerebral structure remained fixed after birth. Soon afterwards, Ramo ´n y Cajal [4] described that, ‘‘in the adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree’’. However, in the first half of the 20tth Century, some authors suggested the existence of a cerebral mitotic process in rats after birth [5–7], but did not clearly identify whether such dividing cells became neuronal or glial cells. Studies about neurogenesis advanced after the development of the autoradiography technique with [3H]-thymidine, which is incorporated into the DNA of proliferating cells. Joseph Altman used this technique and demonstrated the occurrence of neurogenesis in several cerebral structures of young and adult rats, such as in the dentate gyrus [8], neocortex [9], and olfactory bulb [10]. Altman argued that those new neurons were ‘‘microneurons’’ – granule or stellate cells with short axons – and suggested that they played a role in learning and memory processes. Techniques available at that time were incapable of accurately demonstrating whether those cells were neurons or glial cells, and, therefore, Altman results were ignored. However, after the development of electronic microscopy, Kaplan showed that the cells in the dentate gyrus and olfactory bulb of adult rats that incorporated [3H]-thymidine had ultrastructural characteristics of neurons [11]. Finally, significant advances in the study of neurogenesis occurred in the 1990s, with the development of the synthetic analog of thymidine, BrdU (5-bromo-30 -deoxyuridine). BrdU is incorporated into cells in the cell synthesis phase (mitosis S phase) and is, therefore, a marker of cell proliferation. Cell nuclei marked with BrdU may be visualized using immunohistochemical techniques, which does not require the use of autoradiography [12]. In most of the CNS regions in mammalians, the appearance of new neurons is a process limited to embryogenesis [13], and once development is complete, progenitor cells that originated from neurons go through a differentiation process and become incapable of division. However, the neurogenesis process in the CNS of adults has been described in several species, such as crustaceans [14], reptiles [15], amphibians [16], birds [17], rodents [8], primates [18] and human beings [19]. In all the mammalian species already studied, including humans, the mitotically active progenitor cells, capable of generating new neurons in the adult
353
phase, are located in specific regions [19,20]. These regions are the ventricles, specifically the subventricular zone of the lateral ventricles (SVZ) and the hippocampal formation, specifically the subgranular zone of the dentate gyrus (SGZ) at the point where the internal layer of granule cells of the dentate gyrus meets the hilus. In the SVZ, 30,000 new cells are generated bilaterally per day in adult mice [21]. These cells migrate towards the olfactory bulb along a well-defined pathway, called the rostral migratory stream (RMS), a process that takes about 2–6 days [21–23]. After reaching the olfactory bulb, these cells migrate radially towards the cell layers, where they differentiate into a large variety of cell types, such as periglomerular neurons and interneurons, as well as astrocytes and oligodendrocytes [21] (Fig. 1). Although it is unknown why the olfactory bulb needs such a considerable number of new cells, it is easier to speculate the reason why the hippocampal formation needs them: This encephalic region is crucial for the acquisition and retention of new information. Therefore, the greater the number of cells, the more efficient the cognitive processes will be. Studies that investigated neurogenesis in the hippocampal formation showed that, of the principal neuron populations in this region, the granule cells of the dentate gyrus are the ones that retain a mitotic capacity postnatal [8,18]. Most granule cells of the dentate gyrus are generated in the postnatal period. However, the full development of the granule cell layer occurs between the 20th and 25th days of life. Granule cells are originated from progenitor cells located in the hilus of the dentate gyrus. They are initially spread all over the hilus, and, in the second postnatal week, they are found in the SGZ of the dentate gyrus, where they remain mitotically active. In most organisms, this process may persist for substantially long peri-
Figure 1 Sagittal view shows neurogenesis sites in the olfactory bulb-subventricular zone system. Cells proliferate in the subventricular zone and migrate along the rostral migratory stream to the olfactory bulb, where they differentiate. Adapted by permission of [1].
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Figure 2 Frontal view of rodent brain shows sites of neurogenesis in the dentate gyrus (DG) in the hippocampal 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].
ods, maybe until senescence [24]. For example, in adult rats and monkeys, the progenitor cells are found in the SGZ of the dentate gyrus; in rats, 9000 new cells are generated by day [25], whereas this number is 200 in monkeys [23]. These new cells proliferate and migrate continuously into the granule cell layer [26]. In this region, they develop a morphology that is typical of granule cells [27], express neuronal differentiation markers [26], and extend their axons to the pathway of mossy fibers, which project into the CA3 region of the hippocampus [28]. This process of integration into an already existing circuitry lasts about 4–8 weeks [29] (Fig. 2).
Neurogenesis in the amygdala: a new etiologic hypothesis for autism? Autism is a pervasive developmental disorder characterized by impairment of social interaction, verbal and nonverbal communication, restricted activities and interests, and stereotyped behavioral patterns [30,31]. The causes of autism are still unknown, and the neuropathologic processes associated with it are not well-defined. Because of the complexity of symptoms of individuals with autism, it is believed that several of their cerebral regions have morphofunctional changes, which justify the phenotypic diversity among patients. Of the different cerebral regions that have been associated with autism, the amygdala has been the focus of a large number of studies [32]. The amygdala, one of the key structures of the limbic system, is a heterogeneous region formed by several nuclear sub regions, including the basolateral and the corticomedial regions, which have different connections and structural characteristics. The amygdalar complex seems to play a central role in emotional, motivational and social processes, and is crucial to assign emotional significance to everyday experiences [33].
Studies using animal models suggest that the amygdala is an important station in the pathway of information responsible for social recognition processes [34]. The incapacity to store knowledge of meetings with co-specifics in the memory determines an important impairment in the capacity of regulating social interactions. Along the phylogenetic development, recognition mediated by the olfactory system, through the pheromonal recognition found in mammalians, became primarily managed by the visual and hearing systems in primates. In human beings, the improvement of this ability required the specialization of certain regions, such as the fusiform gyrus, the amygdala, and the superior temporal sulcus. Studies that focused on these areas, which are activated in human face and voice recognition tasks, show that these regions, though activated in normal controls, are not activated in patients with autism [35,36]. The development of more sophisticate and accurate functional cerebral imaging techniques, such as proton emission tomography (PET), single-photon emission tomography (SPCT) and functional magnetic resonance (fMRI), have opened the way to new and promising investigations of cerebral dysfunction in autism [31]. However, the evaluation of the structure of the amygdala using these techniques yielded controversial results. Howard and colleagues (2000) used quantitative MRI and found an increase in the volume of the amygdala in patients with autism. Their data were confirmed two years later by Sparks and colleagues [37], who also found an increase in the volume of the amygdala in 45 children with autism, in a study using three-dimensional MRI. However, Aylward and colleagues (1999) found a reduction in the volume of the amygdala in 14 teenagers with autism in an MRI study. A recent study conducted by researchers in the Department of Psychiatry of the University of California used postmortem stereological measurements and showed a decrease in the number of neurons in the amygdala of 9 teenagers and adults with autism [38].
Neurogenesis in the amygdala: A new etiologic hypothesis of autism? Despite some gaps in knowledge, it may be suggested that the amygdala shows structural changes in association with autism [39]. This region plays an important role in learning and memory, particularly of the repertoire necessary for the adequate establishment of social skills [40]. Learning and memory take place by the formation of new neural connections, and require a plastic capacity to rearrange information [41]. Such plasticity is even more demanded in the formation of neuronal circuits that enable social behaviors because it is necessary to group dozens of different stimuli (each with its neuronal network) to construct the social memory and its accompanying affective and temporal meanings, for example. Therefore, neurogenesis and neuronal plasticity may have an important role in the dynamics of social functioning, and the morphologic and functional changes found in the amygdalar structure seem to reflect the unbalance of these processes. Before we explore the hypothesis of impairment in neuronal plasticity, morphologic changes in the amygdala and social impairment, we should go back to the formation of new neurons in adult nervous tissues. Two specific encephalic regions (SVZ, SGZ) are reported to be capable of generating new neurons in adult life [19,20]. However, other cerebral structures, such as the amygdala, have also been associated with neurogenesis in the adult nervous system [1,42,43]. It becomes opportun to explore the association between neurogenesis in the amygdale [43,44] and the morphofunctional changes of this structure in understanding the dysfunctional aspects found in the development of sociability in children with autism. How this association takes place is a challenge for future investigations. Some studies showed an increase in the volume of the amygdala, and suggested either an increase in neurogenesis or a decrease in neuronal pruning [45]. At the same time, other studies reported a decrease in the volume of the amygdala [46], which reinforces the idea that the neuronal plasticity of people with autism is affected in the amygdalar region. What impact, therefore, would such changes have on neuronal plasticity of the amygdala and on the social performance of an individual? Evidence shows that new neurons have a more relevant role in learning tasks that have a greater emotional content, tasks that require the activation of the hippocampus and the amygdala, differently from the pattern found in tasks of visual and spatial learning, which do not require the activation of the amygdala [47]. Interestingly, in the presence of GABAergic stimulation, there is a decrease in long-term potentiation particularly ob-
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served in mature granule neurons, an effect that may be reverted by the action of GABAergic blockers. However, young neurons are not inhibited by GABA, which may justify the recruitment of this type of cell for learning experiences in new environments when the level of GABA is increased [48]. Therefore, the following scenarios may be considered: (1) the amygdala decisively contributes to the establishment of learning tasks associated with emotional meaning, (2) this learning takes place primarily by recruiting new neurons and (3) these neurons are less sensitive to decreases in the GABA-induced activation. The amygdala has two different embryonic origins that form two portions, a cortical and a striate one [49]. These portions are formed by different nuclei, which seem to act in different ways. For example, a number of studies demonstrated that the medial portion of the amygdala is an important site in the circuit responsible for social recognition memory [50]. The nucleus located in the striate portion of the amygdala seems to be responsible for a primitive function necessary for the establishment of social groups among mammalians. This simply memory is relevant among other, to regulate the hierarchical behaviors. At the same time, the basolateral nucleus of the amygdala, located in the cortical portion, plays a role in contextual memory and is relevant to imprint the meaning of the experiences learned [51]. In sum: in the amygdala, the ability to acquire meaning from new experiences is modulated by GABA and requires non-mature neurons. It is interesting to note that individuals with autism have important changes in the GABAergic system [52]. The decrease of this neurotransmitter seems to have an effect on cerebral organization, which results, for example, in changes in neuronal migration [53] and organization of GABAergic interneuron’s, and which compromises the inhibitory system in these patients [54]. We may, therefore, 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 the amygdala and on its capacity to store new experiences [47,48] and to modulate the plasticity of the corticostriatal connections [55]. The decrease in neurons found in a postmortem study confirms this hypothesis [38]. Recent studies have demonstrated that neurogenesis in the CNS of adults is markedly affected by a large number of stimuli. Therefore, strategies may be adopted to improve the mitotic process in the amygdalar complex of people with autism.
356 One of these strategies would be physical activity. Henriette van Praag and colleagues [56] showed that physical activity increases cell proliferation, survival and neurogenesis in the hippocampal formation of mice. These data suggest one more beneficial effect of the daily practice of physical activity, and may explain why individuals that practice exercises regularly have a better cognitive performance. One of the interventions proposed for individuals with autism is a method based on a physical activity program, the Higashi method [57]. However, no clinical trials have shown the advantages of this methods over others currently used. Moreover, it seems to be clear that not all demands observed in people with autism may be met by using this method. However, it is possible that some of the impairment found in a subgroup of people with autism may be reversed by an increase in neurogenesis and plasticity in certain cerebral regions.
Conclusion The hypotheses that were discussed in this paper suggest that neurogenesis may be involved in the physiopathology of autism. Therefore, interventions to increase neurogenesis may become one more therapeutic alternative for this pervasive developmental disorder. Undoubtedly, although this model may explain processes in some individuals with autism, it is not sufficient to understand all the signs and symptoms observed in these cases or all the possible subgroups of individuals with autism. However, neurogenesis may be a new paradigm for the understanding of part of the biological processes associated with autism. As most of our suggestions are still speculative, studies with animals should be conducted to investigate the neurogenesis-autism hypothesis. Moreover, we suggest that this hypothesis be evaluated using specific markers for cell proliferation, migration and differentiation in necropsy encephalic tissues of patients with autism. If confirmed, this hypothesis may lead to the formulation of new therapeutic approaches to autism.
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