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Dana et al. J Transl Genet Genom 2020;4:251-62 I http://dx.doi.org/10.20517/jtgg.2020.25 Page 257
[92]
to contribute to ASD development via the IGF1/PI3K/AKT/mTOR pathway . Accordingly, it was
assumed that autophagy will increase or decrease through PI3K/AKT/mTOR, thereby contributing to the
development of ASD. Based on this assumption, VPA was given to rats and it was observed that the rats
[46]
had autistic-like behaviors. Zhang et al. rats were given VPA and autistic-like behaviors were observed.
Various autophagic markers were examined in the hippocampus of these rats by the immunohistochemical
method and mTOR inhibition was found to increase PI3K/AKT/mTOR-mediated autophagic activity.

Sphingosine 1-phosphate (S1P) is abundant in the brain tissue and plays an important role in brain
[93]
development, regulation of neuronal differentiation, proliferation, survival, and apoptosis . There
is growing evidence that abnormal S1P levels are associated with the pathogenesis of schizophrenia,
[94]
Alzheimer’s disease, and anxiety disorder . In a study that investigated the pathogenesis of S1P in autism,
a VPA rat model was used to evaluate S1P expression levels in the serum and brain tissue. Expression of
autophagic proteins Beclin-1, LC3-II, and P62 were investigated in rats exposed to VPA. The investigators
[95]
in the study found that increased S1P may be associated with decreased autophagy in this model . A
study was carried out to illuminate the link between the Notch signaling pathway and the pathogenesis
of autism. They also investigated whether 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester
(Dapt) caused autism relevant behavior in the VPA rat model by regulating autophagy and affecting the
morphology of dendritic spines. Autophagy-dependent proteins LC3B, Becn1, and phospho-p62 were
inhibited by Dapt in rat VPA model in the hippocampus, cerebellum, and prefrontal cortex. The Notch
signaling pathway participates in the ASD pathogenesis by affecting dendritic spine growth and regulating
[96]
autophagy .

CC2D1A models for autism
The CC2D1A (coiled-coil and C2 domain-containing 1A) gene is one of the new candidate genes associated
[4]
with autism . In humans, the CC2D1A gene mutation was first associated with autosomal recessive
[97]
nonsyndromic intellectual disability . This means that the CC2D1A gene has a function in the central
nervous system. Cc2d1a knock-out mouse model has been shown that regulates multiple intracellular
signaling pathways, involved in neuronal differentiation and brain development, activators of Protein
Kinase B (PKB), and NF-κB [98,99] . CC2D1A protein consists of a COOH-terminal C2 domain and NH2-
terminal domains. The CC2D1A gene family consists of two homologous units, CC2D1A and CC2D1Bfor
both humans and mice. The CC2D1A protein has two main isoforms containing 950 and 388 amino acids.
The shorter isoform of the protein does not include exons 14 to 16, which are deleted in patients with
ASD. Therefore, only the long protein isoform plays a central role in disease pathogenesis in the patients.
The most conserved motif is a C2 domain and the other motif, DM14, is unique to the CC2D1A protein
family, but its role is unknown. The C2 motif is located at the C-terminus of CC2D1A at positions 661-762,
and is found in proteins that function in calcium-dependent phospholipid binding, where the C2 domain
2+
itself participates in the binding pocket of the Ca cation. The DM14 motif repeats four times in the
human CC2D1A sequence but only three times in the Caenorhabditis elegans orthologue sequence. The
DM14 motif also appears only in the long isoform of CC2D1A, while the C2 domain is present in both
isoforms, suggesting that it probably plays a central role in its protein activity [100-103] . The CC2D1A gene
functions to bind to DNA and suppress transcription of serotonin receptor 1 A (HTR1A). The physiological
role of the CC2D1A gene is not fully known. In a study, CC2D1A knock-out mice were produced to
examine this role. Mice with the homozygous CC2D1A gene mutation died immediately after birth due
to their inability to breathe, while mice with the heterozygous mutation remained alive and productive.
Therefore, since the CC2D1A gene is vital, the absence of this gene as in the homozygous case is fatal [104] .
The absence of the CC2D1A gene primarily affects brain function. Studies with animal models have
revealed that this gene has a role in the regulation of endosomal traffic and signaling pathways. Disruption
of this gene affects numerous biochemical pathways including cAMP response element-binding protein
(CREB), NF-κB, protein kinase A (PKA), protein kinase B (PKB/AKT), Notch, and BMP [100] . CC2D1A