Download Soltis Autism: a Spectrum of Research Abby Soltis Final Draft Senior

Soltis
Autism: a Spectrum of Research
Abby Soltis
Final Draft
Senior Capstone Paper
12/9/11
Cell Biology Capstone
Dr. Maloney
Butler University
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Introduction
Autism was first described in 1943 and characterized as a behavioral disorder caused by
“refrigerator mothers,” who were cold and distant toward their children causing the children to become
socially awkward and slow developing (Bauman, 1991). Nearly 70 years later, autism terminology has
changed to autism spectrum disorder, ASD, and the label has changed from a behavioral disorder to a
pervasive developmental disorder (Yip et al., 2007). While this disorder is no longer believed to be
caused by poor mothering, the actual causes of autism are largely unknown, but hypothesized to be
associated with genetics and environmental factors such as complications during pregnancy or birth,
metabolic conditions or viral infections (Fatemi et al., 2002a; Lee et al., 2002). In 1998, 2001, 2007, and
2010 the prevalence rate of autism in the population was reported to be 4/10,000; 1/1,000; 1/152; and
1/160 respectively (Bailey et al., 1998; Fatemi et al., 2001; Kulesza and Mangunay, 2008; Giza et al.,
2010). The most recent information from the Center for Disease Control from 2010 suggests that 1/ 110
children in the United States is diagnosed with ASD. The number of diagnosed cases of autism spectrum
disorder has increased per number of births, in turn increasing the importance of research regarding this
disorder.
Due to the lack of consistent genetic markers in autism, the current diagnosis of ASD relies on
three categories of deficits: communication, social interaction, and repetitive behaviors (Lord, 2011).
External physical properties, such as microcephaly and brain structure malformation occur in 30% of
autism spectrum disorder cases (Palmen et al., 2004; Wegiel, et al., 2010). Communication deficits and
social interaction deficits are characterized by delayed language development, abnormal social responses,
lack of eye contact, and language abnormalities (Yip et al., 2009; Fatemi et al., 2002a). Repetitive
behaviors associated with autism generally function to control the environment or access certain stimuli,
as well as insist on sameness (Martin et al., 2010; Fatemi et al., 2002a).
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Due to the reliance of behavior for diagnosis, the disorder is not typically confirmed in children
until the age of 3 or 4, although many of the behaviors can be identified much earlier (Fatemi et al.,
2002a). Another well-documented characteristic of autism spectrum disorder is the prevalence of the
disorder in males; as many as 3 to 4 times more males are diagnosed with ASD than females (Purcell et
al., 2001). In addition to these behavioral identifiers, people diagnosed with autism are more likely to
have hyperactivity, epilepsy, sensory processing abnormalities, and mental retardation (Peñagariko et al.,
2011; Giza et al., 2010). Fragile X syndrome, Rett syndrome, Down syndrome and tuberous sclerosis are
also associated in 5-10% of ASD cases (Wegiel et al., 2010). The hyperactivity present in children with
ASD is associated with several repetitive behavior disorders. This hyperactivity manifests as attention
deficit disorder, which is co-morbid in 30% of children diagnosed with ASD (Martin et al., 2010). ASD is
co-morbid with epilepsy in 25% and 33% of cases and mental retardation in 75% and 44.6% of cases, yet
advanced mental capacity was also observed (Lee et al., 2002; Wegiel et al., 2010; Fatemi et al., 2002a).
The broad spectrum of autism is thought to be the result of several, non-overlapping genes, many
of which will be mentioned in this review of research (Wegiel et al., 2010). Due to the diversity in
symptoms and the many diseases that either occur with or are similar to ASD, many pathways and areas
of the brain have been studied in regards to autism. The study of these pathways, most notably that of the
GABAergic system, has implications for not only the discovery and treatment of autism, a disorder
increasing in prevalence, but the discovery of the mechanism through which acetylcholine and its many
counterparts function in the brain. The research overviewed in this paper in regards to autism addresses
Purkinje cell decreases, GABAergic and Cholinergeric system abnormalities, and developmental
abnormalities.
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Purkinje cells
Perhaps the most well documented abnormality associated with autism is in regards to the
Purkinje cells located in the brain. Fatemi et al. (2002a) showed an average of 24% decrease in Purkinje
cell size of 5 individuals with autism when compared to 5 control individuals. The authors hypothesize
that the decreased Purkinje cell size is due to atrophy, and a subgroup of younger individuals with autism
would show less atrophy. Lee et al. (2002) also observed a decrease in Purkinje cells in cases of autism. A
more pronounced Purkinje cell loss was observed in the autistic case co-morbid with epilepsy, however
two autistic cases showed no Purkinje cell loss (Lee et al., 2002). In addition to an overall decreased
Purkinje cell number, researchers have found an uneven pattern of cell proliferation, decreased size of
Purkinje cells, and a decrease in density of Purkinje cells in multiple cases of autism (Bailey et al., 1998;
Lee et al., 2002).
In behavioral studies done with mice, decreased Purkinje cells correlated to a decrease in
learning, therefore Dickson et al. (2010) hypothesizes that developmental cerebellar Purkinje cell loss
may affect higher level cognitive processes, which have been shown to occur in many cases of ASD.
Studies have also been done linking repetitive behaviors in mice to a decrease in Purkinje cells, where
mutant mice with few Purkinje cells showed more repetitive level pressing than all mutants and control
mice (Martin et al., 2010). Most studies done regarding Purkinje cell loss have been done on cases where
mental retardation occurred with the autism, raising the question whether autism or mental retardation is
the cause of Purkinje cell loss (Lee et al., 2002). The current body of research suggests that the
abnormalities associated with Purkinje cells are likely a secondary effect of developmental delays in the
brain, as well as abnormalities in the Cholinergic and GABAergic system discussed later in this paper
(Bailey et al., 1998).
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GABAergic system.
Gamma-aminobutyric acid or GABA is an inhibitory neurotransmitter in the central nervous
system that is part of the GABAergic pathway (Yip et al., 2007). GABA is known to affect locomotor
activity, learning, reproduction and circadian rhythms. The disruption of this pathway will impact normal
memory transmission to and from certain areas of the brain, which could lead to several of the neurodeficits associated with autism (Fatemi et al., 2002b). The GABAergic pathway has already been
associated with several diseases including schizophrenia and bipolar disorder, which are specifically
associated with the down regulation of GAD67 and GAD65.
Glutamate decarboxylase or GAD67 is an enzyme aiding in the formation of GABA from Lglutamate and is regulated by GABA levels. Therefore GAD67 indicates GABAergic activity (Yip et al.,
2007). Previous research has indicated the presence of a susceptibility locus for autism located at the
2q21-q33 region. GAD67 is encoded on chromosome 2q31.1, which is located in the susceptibility locus,
providing more evidence that GAD67 is a good candidate for autism research (Yip et al., 2007).
Additionally, GAD67 is strongly expressed in Purkinje cells. Yip et al. (2007) showed that 8 brains from
patients diagnosed with varying degrees of autism, when age-matched with 8 normal brains, showed a
decrease in GAD67 mRNA in Purkinje cells by 40%. Previous studies have already indicated a decrease
in the GAD67 protein by 51%, and 61% in cerebellar and parietal areas of the brain, so a mirrored
decrease in GAD67 mRNA shows that the cause of the decrease in GAD67 protein occurs in the pathway
before transcription (Yip et al., 2007). GAD67 decreases have also been reported in schizophrenia,
bipolar disorder, and major depression in addition to autism (Fatemi et al., 2002b; Yip et al., 2007; Yip et
al., 2009).
Additional research has also been done regarding the effect of glutamate in the GABAergic
pathway. Purcell et al. (2001) identified an increase in glutamate in 9 autistic brain samples in comparison
to 18 control brain samples. The high level of glutamate could indicate low levels of GABA, resulting in
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low levels of GAD67. While glutamate has been shown to initiate seizures, in this study there was no
correlation between glutamate levels could be found, perhaps due to the small sample size (Purcell et al.,
2001). Glutamate receptors are located in the cerebellum and hippocampus. Both regions, which have
been repeatedly implicated as containing abnormalities in autistic brains (Purcell et al., 2001).
GABAergic cells in the cerebellum appear early in embryonic development, but occur in only
20% of adult levels at birth. One possible explanation for decreased GAD is that the GABAergic system
never fully develops (Yip et al., 2007). Another possible explanation is that olivocerebellar climbing
fibers in the neurons are sending increased excitatory input to Purkinje cells and thus down regulating
GAD67 (Yip et al., 2007). Alternatively, another hypothesis is that dopamine is causing a down
regulation of GAD67 after its receptors are stimulated and the NMDA receptors are blocked by an
agonist, as seen in the rat model (Yip et al., 2007). Purcell et al. (2001) indentified an abnormality in the
concentration and number of NMDA-glutamate receptors in the cerebellum. If these NMDA receptors are
decreased in number, mimicking the blocked NMDA glutamate receptors in the rat model, and paired
with an excitation of the dopamine receptors, this could cause a down regulation of GAD67, a subunit of
the GABAergic pathway. The NMDA glutamate receptor is required for long-term learning and memory,
so perhaps the involvement of the NMDA-glutamate receptor could explain some of mental retardation
and learning disabilities associated with autism. A possible proposed treatment is blocking some of
NMDA receptors, with an agonist, which has been observed to have a calming effect on children with
autism (Purcell et al., 2001). Further studies have not been done regarding this treatment possibility.
Another type of glutamate receptor, AMPA receptor, showed decreased density in the 9 autistic
brains when compared to the autism controls. GRIP and 4.1N proteins, which are responsible for
glutamate receptor localization, were also shown to have decreased levels and therefore may be the reason
for decreased glutamate AMPA receptors (Purcell et al., 2001). In addition to altered AMPA receptors the
GABA pathway also showed an increase in the EAAT1 and 2 protein levels in the cerebellum, proteins
responsible for removal of glutamate from the extrasynaptic space; this increase may be a secondary
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effect of increased glutamate (Purcell et al., 2001). GABAA, another GABA receptor, has shown
decreased levels in the brain in the hippocampus, which indicates an improper development of neurons
addressed later in this paper (Blatt et al., 2001). A possible cause for reduced AMPA receptors may stem
from the deletion of the SHANK3 gene near the terminus of chromosome 22q is linked with the Islet
Brain-2 gene, which, when the gene function is disrupted, reduces AMPA, enhances NMDA receptormediated glutamergic signaling, and changes the morphology of Purkinje cells, all leading to cognitive
deficits associated with autism (Giza et al., 2010).
Another study done by Yip et al. (2009) looked at the role of a different GAD isoform, GAD65,
in the GABAergic system in regards to autism (Yip et al., 2009). Previous research regarding GAD65 has
shown a decrease in the protein by 48% and 50% in the parietal and cerebellar cortices of autistic brains
respectively (Fatemi et al., 2002b). GAD65 levels have been associated with anxiety and schizophrenia, a
disease closely associated with autism (Yip et al., 2009). The gene locus for GAD65 is 7q21.3, which has
also been implicated in autism (Yip et al., 2009).
Dentate nuclei, which receive input from Purkinje cells, should have a decreased output in autism
due to the plethora of research regarding a decrease in Purkinje cells. However, the function of dentate
nuclei remain largely unchanged, so therefore the mechanism of the GABA pathway is being examined in
order to consider how this pathway is functioning despite the Purkinje cell deficit (Yip et al., 2009). Yip
et al. finds that GAD65 is associated with two subgroups of neurons, large-sized and smaller-sized,
however GAD65 is reduced by 51% in the large sized and unchanged in the small-sized, suggesting that
there is a misfiring of these neurons in the cerebellum associated with autism (Yip et al., 2009).
Interneurons associated with the GABAergic pathway have also shown to have abnormalities in
autistic cases. In the hippocampus, GABAergic internuerons stained with parvalbumin, calbindin, and
calretinin, were identified to have an increase in density in 5 autistic cases in comparison to and 5 control
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cases (Lawrence et al., 2009). This may be related to the down regulation of GABAA receptors (Lawrence
et al., 2009).
While much research has been done regarding this GABAergic pathway, it is difficult to ascertain
the initial cause of the multiple abnormalities in the cerebellum associated with autism, the majority of
which have some impact on the decrease in Purkinje cells. Before any possible treatment can arise from
this research, more information is needed regarding the GABA pathway, especially because brain
development is so sensitive to glutamate levels (Purcell et al., 2001). One of the largest limitations with
GABAergic system abnormalities and all autism research is small sample size, so before any treatments
are developed replication must be done with a larger sample size (Bailey et al., 1998; Peñagariko, 2011).
One current hypothesis is that since it is likely that impairments associated with autism occur during early
brain development, alternative pathways are being utilized, which could explain some of the changes seen
in the GABAergic pathway (Yip et al., 2009). Perhaps the most important effect of the GABAergic
system in regards to autism is the implication for neuronal development delays. Whether the GABAergic
system is the cause or the effect of this neuronal development deficiency is unknown (Bailey et al., 1998).
Cholinergic System Abnormalities
Choline acetyltransferase, a necessary protein associated with the formation of acetylcholine, has
been shown to be highest in the fetal brain, declining into adulthood. Transversely, acetylcholine
receptors, such as muscarinic and nicotinic receptors decrease into adulthood (Lee et al., 2002).
Previously, abnormal binding of acetylcholine to the acetylcholine receptors has been shown, so specific
muscarinic and nicotinic receptors were studied to see if abnormal binding occurs in autistic cases.
Muscarinic receptors were found to have no difference in binding associated with autism in the
cerebellum, however a decreased binding by 30% to the M1, muscarinic receptor in 7 autistic cases when
compared to 11 control cases (Perry et al., 2001; Lee et al., 2002). Lee et al., found that high affinity
nicotinic receptors, consisting of the 4 subunit, showed a 40-50% decrease in number in the cerebellum
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of 8 autistic brains when compared to 10 control brains (Lee et al, 2002). Decreased levels of binding to
the high affinity receptor were also present in the parietal cortex (Perry et al., 2001). Transversely, there
was an increase in binding to the low affinity nicotinic receptor, consisting of the 7 subunit in the same
autistic brain samples (Lee et al., 2002). This suggests that altered receptor structure, presence of the 7
or 4 subunit, may play a factor in low affinity and high affinity nicotinic receptor binding.
Nicotinic receptors in the cerebellum and other parts of the brain are known to cause an increase
in GABA, therefore this abnormality could affect or be caused by the abnormalities already described in
several aspects of the GABA pathway. In addition to the role of the nicotinic receptors in the GABA
pathway, nicotinic receptors have been associated with autism for several other reasons. The 4 subunit
in nicotinic receptors is associated with pain perception; low levels of this receptor could be associated
with the low reactivity to pain found in ASD (Perry et al., 2001). The 7 subunit in nicotinic receptors
has been shown to be associated with chromosome 15q11-15 region, another susceptibility genome locus
associated with autism (Perry et al., 2001). Additionally, nicotinic receptors are shown to be associated
with attentional function and are key players in brain development; deficits in both of these areas have
been observed in ASD (Lee et al., 2002). The decrease in M1 muscarinic receptor binding is thought to be
associated with epilepsy, since epilepsy occurs in 40% of the cases of autism, and not purely autism
(Perry et al., 2001). The decreased muscarinic and nicotinic receptors found in autism are also associated
with schizophrenia, which is thought to just occur later in brain development, therefore treatment options
associated with nicotinic and muscarinic receptors may be possible candidates for people with autism
(Perry et al., 2001). The nicotinic muscarinic receptors in cholinergic system have been shown to play a
major role in cortical development, but many of the abnormalities in this system are inconclusive to
whether autism, epilepsy, or mental retardation is the cause of these abnormalities (Palmen et al., 2004).
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Cerebellar and Brain Structure Abnormalities
In autism hyperplasia seems to be prevelant, however both hypoplasia (Purcell et al., 2001) and
normal brain size have also been reported in several studies all using a small sample size (Lee et al.,
2002). One possible explanation regarding the range of brain sizes has been described by Lee et al.
(2002), who found that a positive association between IQ and cerebellum size accounts for much of the
variability associated with autism spectrum disorder (Lee et al., 2002). Studies of cerebellum damage, as
well as cholinergic cerebellar abnormalities, have shown that the cerebellum is associated with
cognitions, behavior, emotion, and the inability to execute rapid attention shifts (Lee et al., 2002).
Additionally, Bailey et al. noted macrocephaly in 4 autistic cases, 2 cases were found during childhood.
The enlarged cerebellum, and brain size are thought to be secondary effects of increased density in
neurons found in several cases of autism (Bailey et al., 1998).
Yet another deficiency of autism is decreased hearing in some cases of the spectrum (Kulesza and
Mangunay, 2008). In a study done by Kulesza and Mangunay (2008), nuclei of neurons in the medial
superior olive of the brain in 5 cases of autism displayed an abnormal geometric pattern when compared
to 2 control cases. This arrangement of nuclei in the neurons allows for proper timing between the two
ears (Kulesza and Mangunay, 2008).
Although much research has been done on the cerebellum in regards to autism, many other areas
of the brain are also implicated in pathological abnormalities. The visible brain abnormalities are all
associated with delays in brain development, so therefore this portion of research identifies the effects of
autism in the brain and is an important starting point to discovering the mechanism by which autism
effects development.
Developmental Abnormalities
Previous research has indicated increased density of neurons, reduced size of neurons and a delay
of neuron growth, all of which indicated a possible problem in neurogenesis, or the development of
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neurons associated with autism (Wegiel et al., 2010). Markers of abnormal neurogenesis are the
increased thickness of the subependymal cell layer, subependymal nodular dysplasia, abnormal growth of
the dentate nucleus, and dysplasia of the granule layer in the dentate gyrus (Wegiel et al., 2010).
Indications of abnormal neurogenesis are associated with epilepsy, autism and mental retardation (Wegiel
et al., 2010). Autism brain pathology shows evidence of abnormal acceleration of brain growth in early
childhood, minicolumn pathology, which is repetition of brain patterns in the neocortex, and stinted
neuron growth associated with brain structure-specific delays in the growth of neurons (Wegiel et al,
2010).
Wegiel et al. (2010) shows in a study involving 13 autistic brains compared with 14 control
brains that neuropathological changes in 92% of subjects with autism reflects multiregional dysregulation
of neurogenesis, neuronal migration and maturation in autism. Wegeil et al. concluded this through
observations of thickening of the subependymal cell layer, dysplasia in the cerbellum and neocortex, and
general hypoplasia (Wegiel et al., 2010). This vast difference in the brain pathology between 13 cases of
autism, shows the high level of variation associated with autism, and may be indicative of the wide
spectrum in ASD (Wegiel et al., 2010). High neuronal density, cortical thickness, abnormal neuron
organization, and malformed inferior olives were also confirmed in other cases of autism, outside of
Wegiel et al.’s research (Bailey et al., 1998).
Neuronal migration abnormalities are associated with the absences of the CNTN2 AP2 gene
located on the 7q35 region of the chromosome (Lord, 2011). Brain pathology tests in mice that are
negative for the CNTNAP2 gene and show deficits in 3 autism related areas, which include abnormal
vocal communication, repetitive and restrictive behaviors, and abnormal social interactions. These mice
as are also prone epileptic seizures and hyperactivity, show abnormal neural migration patterns and have a
reduced number of GABAergic interneurons (Peñagariko et al., 2011). These results support the
hypothesis that the CNTNAP2 gene is involved in early brain development as well as neurogenesis
(Peñgariko et al., 2011). A knockout of the CNTNAP2 gene results in asynchronous neuron firing that
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occurs in neuron signaling. Cognition is associated with neuron firing, therefore the asynchronous neuron
signaling could cause or be attributed to cognition deficits in autism (Peñgariko et al., 2011). Mice with
this gene deficit were treated with Resperidone, a drug used for treatment of schizophrenia, which
decreased the repetitive behaviors in mice. Although further studies must be done, this research
introduced Resperidone as a possible treatment for human cases of autism (Peñgariko et al., 2011).
Reelin, a glycoprotein responsible for normal cell layering, and Bcl-2, a regulatory protein
responsible for programmed cell death in the brain, are thought to be involved in the changes in the
cerebellum, such as decrease in Purkinje cells, associated with autism (Fatemi et al., 2001). 3 autism cases
showed a decrease in Reelin by 43%, 44%, and 44% when compared to age-matched control cases.
Additionally, Bcl-2 showed a decrease by 31% and 54% when compared to age-matched control cases
(Fatemi et al., 2001). These observed decreases may have the ability to alter the cerebellum in autism, due
to Reelin controlling normal layering in the brain and Bcl-2 controlling programmed cell death (Fatemi et
al., 2001).
Conclusion
This compilation of research highlights the diversity in not only the effects of autism, but also the
complexity and sheer number of possible pathways and pathway components that could be secondary
effects of the disorder or possible mechanisms by which autism develops in children. Some of the most
promising research in regards to autism involves the GABAergic and Cholinergic systems (Yip et al,
2007, 2009; Purcell et al. 2010; Lee et al., 2002; Perry et al., 2002). Since autism has been identified as a
genetic disease, several loci have been identified including the 7q35, 2q21-33, 22q regions identified in
this paper (Lord, 2011; Yip et al., 2007; Giza et al., 2010). The next steps in research must question how
this set of un-linked genes can cause the spectrum associated with autism.
As autism research progresses there are multiple barriers being faced in several aspects of
discovery. The lack of a model organism, which exhibits autism is a major concern (Purcell et al., 2001).
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Several studies including Peñgariko et al. (2011), use mice as a model organism for autism research,
however, unless a specific gene is being targeted, behavioral analysis is not a reliable way to compare
autism in humans to autism-like behavior in mice. A second barrier is the lack of choice in age and type
of autism brain samples (Purcell et al., 2001). Since autism spectrum disorder exists at such a wide range,
and limited brain samples are available, all types of autism must be lumped together to get a large enough
sample size for analysis. Another difficulty with autism research is the inability to identify observations in
the brain or the associated pathways as a cause to autism or a secondary effect of autism, especially since
few child cases of autism have been studied.
While much research has been done regarding autism, the body of research remains vastly
unconnected, due to the inability to attribute characteristics to autism or the many diseases that exist in
patients with autism, especially epilepsy. In order to further this body of research, two things must be
done. Firstly, differentiation must occur between autism, epilepsy and other related diseases such as
schizophrenia. Secondly, a connection must be made between the plethora of genes identified in
association with autism. As cases of autism spectrum disorder increase in the population, autism
discovery and treatment must be addressed with new rigor.
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Literature Cited
Bailey, A., P. Lutheret, A. Dean, B. Harding, I. Janota, M. Montgomery, M. Rutter, and P. Lantos. 1998.
A clinicopathological study of autism. Brain. 121:889-905.
Blatt, G.J, C.M. Fizgerald, J.T. Guptill, A.B. Booker, T.L. Kempter, and M.L. Bauman. 2001. Density
and distribution of Hippocampal neurotransmitter receptors in autism: an autoradiographic study.
Autism and Developmental Disorders. 31:537-543.
Dickson, P.E., T.D. Rogers, N. Del Mar, L.A. Martin, D. Heck, C.D, blaha, D. Goldowitz, G. Mittleman.
2010. Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss.
Neurobiology of Learning and Memory. 94: 220-228.
Fatemi, S.H. J.M. Stary, A.R. Halt, and G.R. Realmuto. 2001. Dysregulation of Reelin and Bcl-2 Proteins
in autistic cerebellum. Autism and Developmental Disorders. 31:529-535.
Fatemi, S.H., A.R. Halt, G. Realmuto, J. Earle, D.A. Kist, P. Thuras, and A. Merz. 2002a. Purkinje cell
size in reduced in cerebellum of patients with autism. Cellular and Molecular neurobiology. 22:
171-175.
Fatemi, S.H. A.R. Halt, J.M. Stary, R. Kanodia, S.C. Schulz, and G.R. Realmuto, 2002b. Glutamic Acid
Decarboxylse 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol
Psychiatry. 52;805-810.
Giza, J., M.J. Urbanski, F. Prestori, B. Bandyopadhyay, A. Yam, V. Friedrich, K. Kelley, E. D’Angelo,
and M. Goldfarb. 2010. Journal of Neuroscience. 30: 14805-14816.
Kulesza, R.J., and K. Mangunay. 2008. Morphological features of the medial superior olive in autism.
Brain Research. 1200:132-1137.
Soltis
15
Lawerence, Y.A., T.L. Kemper, M.L. Bauman, and G.L. Blatt. 2009. Parvalbumin-, calbindin- and
calretinin-immunoreactive Hippocampal interneuron density in autism. Acta Neurol Scand.
121:99-108.
Lee, M., C. Martin-Ruiz, A. Graham, J. Court, E. Jaros, R. Perry, P. Iversen, M. Bauman, and E. Perry.
2002. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain.125:1483-1495.
Martin, L.A., D. Goldowitz, and G. Mittleman. 2009. Repetitive behavior and increased activity in mice
with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism.
European Journal of Neuroscience. 31: 544-555.
Peñagarikano, O., B.S. Abrahams, E.I. Herman, K.D. Winden, A. Gdalyahu, H. Dong, L.I. Sonnenblick,
R. Gruver, J. Almajano, A. Bragin, P. Golshani, J.T. Trachtenberg, E. Peles, and D.H.
Geschwind. 2011. Absence of CNTNAP2 leads to Epilepsy, neuronal migration abnormalities
and core autism-related deficits. Cell. 147:235-246.
Perry, E.K., M.L.W. Lee, C.M Martin-Ruiz, J.A. Court, S.G. Volsen, J. Merrity, E. Folly, P.E. Iversen,
M.L. Bauman, R.H. Perry, and G.L. Wenk. 2001. Cholinergic activity in autism: abnormalities in
the cerebral cortex and basal forebrain. Am J Psychiatry. 158: 1058-1066.
Purcell, A.E., O.H. Jeon, A.W. Zimmerman, M.E. Blue, and J. Pevsner. 2001. Postmortem brain
abnormalities of the glutamate neurotransmitter system in autism. Neurology. 57: 1618-1628.
Wegiel, J., I. Kuchna, K. Nowicki, H. Imaki, J. Wegiel, E. Marchi, S. Yong Ma, A. Chauhan, V.
Chauhan, T.W. Bobrowicz, M. de Leon, L.A. Saint Louis, I.L. Cohen, E. London, W. T. Brown,
and T. Wisniewski. 2010. The neuropathology of autism: defects of neurogenesis and neuronal
migration, and dysplastic changes. Acta Neuropathol. 119: 755-770.
Yip, J., J.J. Soghomonian, and G.J. Blatt. 2007. Decreased GAD67 mRNA levels in cerebellar Purkinje
cells in autism: pathophysiological implications. Acta Neuropathol. 113: 559-568.
Soltis
16
Yip, J., J.J. Soghomonian, and G.J. Blatt. 2009. Decreased GAD65 mRNA levels in select subpopulations
in the cerebellar dentate nuclei in autism: an in situ hybridization study. Austim Res. 2: 50-59.
Secondary Sources
Bauman, M.L. 1991. Microscopic neuroanatomic abnormalities in autism. Pediatrics. 87: 791-796.
Lord, C. 2011. Unweaving the Autism Spectrum. Cell. 147: 24-25.
Palmen, S.J.M.C., H. van Engeland, P.R. Hof, and C. Schmitz. 2004. Neuropathological findings in
autism. Brain. 127: 2572-2583.