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Page 256 Dana et al. J Transl Genet Genom 2020;4:251-62 I http://dx.doi.org/10.20517/jtgg.2020.25

Interestingly, a recent study found that increased activity of mTOR and MAPK pathways in the peripheral
blood samples of idiopathic ASD patients. ERK1-2, rpS6, p-eIF4E, and p-MNK1 (components of the mTOR
and MAPK signaling pathways) showed a significant increase in patients with ASD compared to controls.
TSC1, rpS6, p-eIF4E, and p-MNK1 protein expression discriminated patients according to their clinical
[76]
severity . Overactive mTOR signals suppress autophagy in the brains of tuberous sclerosis complex
+/-
+/-
(TSC) 1 and TSC2 mice during postnatal development and decreased autophagy causing an imbalance
in the pruning of the spines in the cortical layer V pyramidal neurons. Dysregulation of autophagy and
its association with impaired spinal pruning may be more common in at least one subset of ASD in Tsc
[45]
mutant mice . TS is a genetic disease caused by mutations in the TSC1 or TSC2 genes and mTOR activity
+/-
[77]
is regulated negatively with these genes . TSC1 mice showed impairments in social interactions and
[78]
hippocampus-dependent contextual fear conditioning . TSC2 mutations created learning and memory
deficits and contextual fear conditioning . Mice carrying a dominant-negative TSC2 mutation had
[79]
[80]
reduced social interactions and preference for social innovations .
Human with mutations in the PTEN gene tend to develop ASD, macrocephaly, seizures, and ID. It
is thought that neurological symptoms associated with the loss of PTEN and other “mTORopathies”
are caused by hyperactivation of mTORC1-mediated protein synthesis. One study with Pten knock-
out mice revealed that rapamycin-mediated inhibition of MTORC1 activity increased behavioral and
neurophysiological abnormalities and showed a reduction in brain size. The group also found that genetic
deletion of mTORC2 activity suppressed seizures, recovered ASD-like behavior and long-term memory,
and normalized metabolic changes of Pten knock-out mice. They found that reducing mTORC2 rescued
[81]
behavioral and neurophysiological abnormalities . The contactin associated protein 2 (CNTNAP2) is the
first widely studied autism susceptibility gene. CNTNAP2 knock-out mice show core ASD-like phenotypes.
By RNA sequencing of CNTNAP2 knock-out mouse, hyperactive Akt-mTOR signals were detected in the
hippocampus. After treatment with mTOR inhibitor rapamycin or Akt inhibitor LY294002, it was reported
that the social deficit was recovered in mice but had no effect on hyperactivity and recurrent/restricted
behavior. Additionally, the effect of rapamycin and LY294002 on social behavior is reversible. Thus, the
hyperactive Akt-mTOR signaling pathway has been identified as a therapeutic target for abnormal social
[82]
behavior in patients with CNTNAP2 dysfunction .
[83]
According to latest study by Lieberman et al. , autophagy is downregulated during postnatal development
following the upregulation of mTOR activity in the mice striatum. In the same study, a VPA model has
been also conducted; autophagy is specifically reduced. They concluded that the impairment of autophagy
is accompanied by impairments in synaptic transmission and social behavior in the late postnatal
-/-
[83]
development in this mouse model . In the TRIM32 model, the authors generated impaired GABAergic
interneurons and leading autism relevant behaviors in mice, concomitant with an increased autophagy
-/-
[84]
mechanism. Therefore, they suggested that theTRIM32 mouse is a novel autism mouse model .
VPA models
VPA is commonly used as an antiepileptic drug. Clinical studies have shown that exposure to VPA in utero
[85]
is associated with cognitive deficits, birth defects, and an increased risk of ASD . Clinical evidence
shows that there is a link between VPA exposure and both cognitive abnormalities and autism. Animal
studies in recent years have investigated anatomical, behavioral, molecular, and physiological changes due
to in utero VPA exposure. The behavioral tests revealed that VPA exposure causes autistic-like behavior
in offspring; these include social behavioral deficits, increased repetitive behavior, and communication
deficits in rodents . In the embryonic period, a single intraperitoneal VPA injection to 12.5-day-old
[86]
female rats causes autism relevant symptoms in their offspring, and the brain structures and biomarker
levels of the offspring are similar to those in autistic patients [87,88] . The VPA model is often used in ASD
studies [89-91] . mTOR, the main marker of cellular metabolism, cell growth, and autophagy, has been reported