Autism
external image autism.pngAutism Disorder is categorized as a subclass of Autism Spectrum Disorder. It is a neurodevelopmental disorder that is often identified by impairment of social skills, communication and repetitive behaviour [1]. Clinical symptoms usually appear between ages 1.5 to 3 [1]. The underlying mechanism of autism is not well understood. Since this is a complex and heterogeneous disorder, potential genetic and environmental factors have been proposed to examine this disorder. For example, specific gene deletion resulting from copy number variations and polymorphisms in several protein encoding genes have been found to increase susceptibility of autism in some individuals [2]. In addition, prenatal exposure to certain chemical agents has also been found to play a role.

Animal models are often used as a way to examine human behavioural conditions. Valproic acid treated rats are found to display autistic-like behaviour [3]. This include deficit in social interaction, communication and repetitive behaviour. However, the shortcoming of this model is that the autistic behaviours are environmentally-induced (through the use of VPA). The Shank3 mutant mice model, on the other hand, provide a genetically based animal model for autism [4]. This model can examine autism from a molecular point of view. In addition to experimental research, several theories have been proposed to explain the behavioural and cognitive deficits in autistic individuals. Some of these theories focus on explaining the symptoms of autism while others focus on the neurobiological ‘uniqueness’ of these individuals. Potential treatment of autism can be proposed by integrating current theories with the empirical research through pharmacological and behavioural intervention.


1.1 Possible Genetic Cause

1.1.1 Copy Number Variants
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Through genetic testing and twin studies, it has been reported that approximately 10% of the autism cases have an underlying genetic component [5]. Recently, de novo copy number mutations have been associated with autism spectrum disorder [5]. The genomes of individuals with autism were compared with their biological parents, there is a high frequency in the spontaneous copy number deletions detected in individuals with autism. However, no common mutations were found between these individuals [5]. The study suggests that genomic changes may play a role in the development of autism, the expression of these genes may vary from one individual to another.




1.2 Possible Environmental Cause

1.2.1 Pre-natal exposure to valproic acid

Valproic acid was first used to treat epilepsy and bipolar disorders [6]. The link with autism spectrum disorder was first identified in the early 1990s when children with Fetal Anticonvulsant Syndrome developed a series of autistic-like behaviours [6]. In a longitudinal study, Rasalam and colleagues found that approximately 8.9% of the participant exposed to sodium valproate prenatally developed either classic autism or Asperger syndrome [6]. This suggests that prenatal exposure to VPA increases individual’s susceptibility in developing ASD.

In recent year, researchers have been trying to identify the exact mechanism of VPA that acts upon in the development of autistic-like behaviour. Kataoka and colleagues showed that VPA exposure in rats increase histone acetylation level, increase cell apoptosis and decrease cell proliferation in the embryonic brain [7]. Since these molecular events occur within the critical period during embryonic development, perhaps these processes are the gateway in understanding the molecular mechanism of autism.


1.3 Neurobiology(Animal Models)

1.3.1 Environmentally-induced Model (valporic acid treated rats)

In the somatosensory cortex and the hippocampus, VPA treated rat showed a significant decrease in BDNF mRNA compare to control rats.
In the somatosensory cortex and the hippocampus, VPA treated rat showed a significant decrease in BDNF mRNA compare to control rats.
Valproic acid(VPA)is often consumed by pregnant mothers as medication for epilepsy and psychological disorders [8]. Rats display behavioural and molecular changes similar to many symptoms exhibited by autism patients after prenatal exposure to VPA.

Schneider and Przewlocki were the first to show that VPA treated rats display a series of behavioural and physiological deficits in various tests [8]. VPA was administered on the 12.5th day of gestation. As compare to control rats, VPA treated rats exhibited a delayed developmental growth (lower body weight, delayed motor movement, delayed nesting response); impaired social skills (low preference for social novelty, lack of engagement with neighbouring animal); and altered nociception threshold (low sensitivity to pain stimuli and enhanced sensitivity to non-painful stimuli) [8]. The behavioural deficit similarities between the VPA rats and the autistic patients further support the validity of this animal model.


More recently, researchers have been focusing on finding molecular signatures in VPA rats exhibiting autistic-like behaviour. Expression of plasticity-related genes such as brain-derived neurotropic factors(BDNF) and NMDA receptors have been linked with social behaviour [9]. Scaccianoce and colleagues found that socially isolated rats reduce the level of BDNF in the hippocampus [10]. In VPA treated rats, BDNF mRNA and NR2A/NR2B receptor expressions were significant reduced in the somatosensory cortex [11]. It is suggested that the altered expressions of in these plasticity-related molecules during early developmental stages can induce autistic-like behaviour in VPA-treated rats. More research is still needed to identify the specific underlying mechanism that mediate this process.

1.3.2 Genetic-linked Model (Shank3 mutant mice)

Researchers have been screening for genetic abnormalities using animal models to uncover the underlying mechanism behind autism. In a recent animal model, the disruption in a post-synaptic protein has been shown to cause autistic-like behaviours in mice [4].
Shank3 protein structure and the behavioural deficits in these knockout mice.
Shank3 protein structure and the behavioural deficits in these knockout mice.

Shank3 is a key post-synaptic protein at excitatory synapses and it functions as a scaffold structure that assists in the glutamatergic signaling pathway [4]. Due to social isolation, Shank3 knockout mice engaged in repetitive grooming and displayed self-injurious behaviour [4]. They exhibited less exploratory behavior and more anxiety-like behaviour in elevated zero maze task and light-dark emergency test [4]. In addition, these Shank3 knockout mice have difficulties with social interaction and novel object discrimination [4]. The repetitive behaviour and the lack of social interaction mirrored some of the symptoms displayed by autistic human individuals. This study does propose a potential genetic marker for screening for individuals with autism.

In addition to the behavioural deficit, Shank3 knockout mice also show an alternation at the molecular level, in particular, in the glutamatergic pathway in the striatum [4]. In Shank3 knockout mice, the expression of scaffolding proteins (such as SAPAP3, Homer and PSD-93 in the PSD protein network) and glutamatergic receptor subunits (such as GluR2, NR2A, NR2B) were greatly reduced compare to the control [4]. The low level of expression of these key proteins resulted in a reduction in post-synaptic response. The mediating pathway of this process is still under investigation, but the disruption in glutamanergic signaling pathway does shine light to a new direction in this field.


1.4 Theories

1.4.1 The Weak Central Coherence Theory

This theory describes individuals with autism have a detailed-focused bias which is often manifested through a superiority in local processing, lacking the global meaning extraction [12]. Narrow interest and exceptional perceptual abilities in autistic individuals are often well-explained by this theory [12]. Deruella and colleagues examined the face processing strategies in children with autism and Asperger Syndrome [13]. Compare to the control, ASD children exhibited a deficit in face processing (this includes decoding emotion, identifying gaze direction, reading lip expression) but intact facial identity recognition [13]. Interestingly, in a separate part of the experiment, when children were asked to complete a face matching task, autistic children outperformed the control when given local facial cues were given (this is contrasted with as global facial configuration cue) [13]. The study suggests that individuals with autism utilize a different perceptual pathway (picking up local cues) compared to normal individuals. This differential processing pathway is further supported by fMRI studies. Both normal and autistic individuals show activation in the fusiform gyri; however, autistic individuals do not seem to engage subcortical regions (amygdala, pulvinar, superior colliculus) involved in face processing [14]. Perhaps other brain regions are involved in the perceptually tuned processing, though more research is still needed in this area.

One criticism for this theory is that it only explains one aspect of autism, the enhanced local processing and reduced global generalization. Perhaps it is more comprehensive to suggest that this theory works together with other cognitive theories to better capture the spectrum of functional atypicalities. The cognitive performance in autism has been associated with various processes. The social cognition 'deficit' is explained by the theory of mind in which it is the inability to attribute mental state of self and others [15]. The behavioural 'deficit' results in a combination of impairment in executive functioning (i.e. higher order cognitive process) and weakness in central coherence (i.e. local processing) [16]. Weak central coherence theory does not account for all of the components of autism, it attempts to explain one cognitive style utilized among autistic individuals on a wide spectrum of phenotypes.

1.4.2 The Empathizing-Systemizing Theory

This theory attempts to explain the social and non-social features of autism by integrating weak central coherence theory and executive dysfunction theory [17]. In addition to the inability to recognize and identify the mental state of self and others (which has been proposed by the theory of mind), there is also the tendency for these individuals to construct systems that help them make future decisions [17]. This theory suggests that it is the imbalance between the affective empathy and systematic analysis that drive the development of autistic conditions. People with autism have a relatively lower score on the Empathy Quotient scale (a measure of the degree of reaction to other people’s thoughts and feelings) and a higher score on the Systemizing Quotient scale (a measure of people’s tendency to generate systems for a given task) compare to control individuals [17]. It is plausible to suggest that the low empathy score is linked with the impaired social and communication skills and the high systemization score is linked with narrow interest and repetitive behaviour.

Similar to the weak central coherence theory, empathizing-systemizing theory explains the detail-oriented cognitive style quite well. Since there is a goal in generating cognitive systems, autistic individuals have a greater need to pay attention to small details in order to manipulate each individual component in the system, this may lead to an exceptional performance in that domain compare to the control [18]. Instead of looking at the detail-oriented processing in autistic individuals through a negative lens, the emphasizing-systemizing theory highlights the strength of this cognitive style. One major criticism of this theory is that it only applies to high-functioning autistic individuals. Empathy processing can be easily measured in low-functioning autistic individuals; however, it is a challenge to measure the constructions of cognitive systems in these individuals.

1.4.3 The Intense World Theory

Hyperexcitation and plasticity in VPA treated rats.
Hyperexcitation and plasticity in VPA treated rats.
This theory attempts to address the wide spectrum of autism disorder through the examination of the cellular and molecular mechanisms. It proposes that autistic individuals have a hyper-functioning neuronal circuit that cause them to respond excessively to various environmental stimuli [19]. The two brain regions characterized by hyper-reactivity and hyper-plasticity are the neocortex and the amygdala [19]. The over-excitation in the neocortex has been proposed to cause hyper-perception, hyper-attention, and hyper-memory; and the over-excitation in the limbic system (i.e. amygdala) has been linked to hyper-emotionality [19]. To avoid this hyper-activity, autistic individuals are more likely to remove themselves from environment that elicit this type of response.

In contrast to the previously proposed theories which suggested that autistic individuals are unable to process social and emotional cues, this theory presents that it is the intense activation in various brain regions that block the appropriate processing of these cues. The repetitive behaviour and narrow interest can also be explained through the exaggerated perceptual processing experienced by these individuals [19]. It is difficult for these individuals to shift their attention from one stimulus to another simply because they are hyper-focused on each component of the incoming information [19]. This amplified perception of the world may persist if it is enhanced by the hyper-activation of the amygdala.
The intense world theory in explaining ASD.
The intense world theory in explaining ASD.

The VPA rat model is often used to examine this “super-charged” brain model. Rinaldi and colleagues found that layer 5 pyramidal neurons in the prefrontal cortex were significant more connected in the VPA treated rats than the control [20]. In addition, it has been found that long-term potentiation is enhanced in neurons located in the somatosensory cortex, the medial prefrontal cortex and the amygdala in VTA treated rats [21]. This theory is still in its elementary stages, the evidence is still limited to the animal models. More research with human autistic subjects are still needed to validity this theory. It is a good starting point to search for a unifying theory that explains the cellular and molecular biology of autism.


1.5 Potential treatment

Through the examination of animal models and current theories on autism, a combination of strategies can be used to treat various symptoms in this neurodevelopmental disorder. Genetic screening such as identification of Shank3 mutation and copy number variant deletions can be used a susceptibility measurement in detecting the development of autism. Once the individual has been diagnosed, a series of pharmacological and behavioural treatment can be used. For example, increasing the level of plasticity-related proteins(such as BDNF) can enhance social cue processing in autistic individuals [11]. At the same time, behavioural interventions can be used to complement the pharmacological treatment. Autistic individuals can learn to acquire global processing strategies through explicit instructions allowing them to integrate individual parts into a functional whole (consistent with the weak coherence theory). They can also generate rules to systematically processing empathy and social cues which in turn enhance their social processing skills (consistent with empathizing-systemizing theory). Moreover, filtering extreme intensity stimuli in the environment or use pharmacological drugs that reduce the intense reactivity of neocortex and amygdala can also buffer the hyperfunctional brain reactivity (consistent with the intense world theory).






References
  1. Kaneshiro, N. K. (2010). A.d.a.m. medical encyclopedia. In Autism (2012 ed.). A.D.A.M. Inc. Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002494
  2. Sebat et al. (2007). “Strong Association of De Novo Copy Number Mutations with Autism”. Science, 316: 445-449.
  3. Schneider, R.P.T. (2004). “Behavoural alterations in rats prenatally exposed to valproic acid: animal model of autism”. Neuropsychopharmacology, 30: 80-89.
  4. Peca, J., Feliciano, C., Ting, J.T., Wang, W., Wells, M.F., Venkatraman, T.N., Lascola, C.D., Fu, Z., Feng, G. (2011). Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature: 472: 437-442.
  5. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, Boris., Yoon, Seungtai., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, Kenny., Wigler, M. (2007). Strong association of de novo copy number mutations with autism. Science, 316(5823): 445-449.
  6. Rasalam, A.D., Hailey, H., Williams, J.H.G., Moore, S.J., Turnpenny, P.D., Lloyd, D.J., and Dean, J.C.S. (2005). Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Developmental Medicine and Child Neurology, 47(8): 551-555.
  7. Kataoka, S., Takuma, K., Hara, Y., Maeda, Y., Ago, Y., and Matsuda, T. (2011). Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. International Journal of Neuropsychopharmacology, 1-13.
  8. Schneider, T., Przewlocki, R. (2005). Behavioural alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology, 30: 80-89.
  9. Branchi, I., D’Andrea, I., Fiore, M., Di Fausto, V., Aloe, L., Alleva, E. (2006). Early social enrichment shapes social behaviour and nerve growth factor and brain-derived neurotropic factor levels in the adult mouse brain. Biological Psychiatry, 60: 690-696.
  10. Scaccianoce, S., Del Bianco, P., Paolone, G., Caprioli, D., Modafferi, A.M., Nencini, P., Badiani, A. (2006). Social isoclation selevtivity reduces hippocampal brain-derived neurotropic factor without altering plasma corticosterone. Behavioural Brain Research, 188: 323-325.
  11. Roullet, F.I., Wollaston, L., DeCatanzaro, D., Foster, J.A. (2010). Behavioural and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience: 170: 514-522.
  12. Happe, F., Frith, U. (2006). The weak coherence account: detail-focused cognitive style in autism spectrum disorders. Journal of Autism and Developmental Disorders, 36: 5-25.
  13. Deruelle, C., Rondan, C., Gepner, B., Tardif, C. (2004). Spatial frequency and face processing in children with autism and Asperger syndrome. Journal of Autism and Developmental Disorder, 34: 199-210.
  14. Kleinhans, N.M., Richards, T., Johnson, L.C., Weaver, K.E., Greenson, J., Dawson, G., Aylward, E. (2011). fMRI evidence of neural abnormalities in the subcortical face processing system in ASD. Neuroimage: 54: 697-704.
  15. Baron-Cohen, S., Leslie, A.M., Frith, U. (1985). Does the autistic child have a ‘theory of mind’? Cognition, 21: 37-46.
  16. Pellicano, E. (2010). Individual differences in executive function and central coherence predict developmental changes in theory of mind in autism. Developmental Psychology, 46: 530-544.
  17. Baron-Cohen, S. (2009). Autism: the empathizing-systemizing theory. Annals of the New York Academy of Sciences, 1156: 68-80.
  18. Jolliffe, T., Baron-Cohen, S. (2001). A test of central coherence theory: can adults with high functioning autism or Asperger Syndrome integrate fragments of an object. Cognitive Neuropsychiatry, 6: 193-216.
  19. Markram, K., Markram, H. (2010). The intense world theory –a unifying theory of the neurobiology of autism. Frontiers in Human Neuroscience, 4:1-29.
  20. Rinaldi, T., Perrodin C., and Markram, H. (2008). Hyper-connectivity and hyper-plasitcity in the medial prefrontal cortex in the valproic acid animal model of autism. Frontiers in Neural Circuits, 2:4.
  21. Markram, K., Rinaldi, T., LaMendola, D., Sandi, C., Markram, H. (2008). Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology, 33:901-912.