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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 255
[53]
genes during embryonic and postnatal development, including neurogenesis-crucial genes and BECN1 .
Given the direct relationship between ADNP and MAP1-LC3B, as well as the connection of autism with
eukaryotic initiation factor 4E (Eif4e) and its tight relationship with autophagy, ADNP is also inevitable to
play a role in autism and autophagy [51,54] . ADNP knock-out mice resulted in embryonic death during the
[55]
[53]
closure of the neural tube . ADNP +/- male mice showed cognitive deficiencies in behavior tests .
ANIMAL MODELS ON AUTOPHAGY: A PERSPECTIVE FROM AUTISM
An ideal animal model of a human disorder should present some characteristics features of the disease.
The model should resemble the symptoms of human disorder and can be genetically modified by specific
[16]
stimulation. Both the models and human patients should respond similarly to certain treatments . Animal
models can provide an advantage over human studies by allowing controlled testing of the effects of specific
[56]
disease-causing factors on synaptic function and behavioral outcomes .
Many of the known genetic variations which contribute to the risk of ASD affect the expression of
proteins that have roles in the chromatin remodeling or function, formation, and maintenance of
[57]
synapses . Deletions of such genes in animals can cause a behavioral phenotype reminiscent of ASD with
impairments in communication, social interaction, and repetitive behaviors . Knock-out models that
[56]
include monogenic ASD genes are NRXN1, MECP2, NLGN3, SHANK3, NLGN4, FMR1, and TSC1/2 [45,58-64] .
Although there are few neuropathological data available in some models, there is growing interest of
carrying specific ASD genes. The emerging risk genes are as follows: CHD8, SCN2A, SYNGAP1, DSCAM,
and TBR1 [65-69] . In the literature, there are syndromic animal models (i.e., Rett Syndrome, Prader-Willi, and
Angelman Syndromes, fragile X, and Tuberous Sclerosis Complex) and environmental animal models [i.e.,
valproic acid (VPA), maternal autoantibodies, and maternal immune activation] that can be generated. In
this review, the most studied mTOR related models and VPA models related to autophagy are discussed.
Also, we explain the developments in the coiled-coil and C2 domain containing 1A (CC2D1A) animal
models, which are not well-known in the literature, through the autophagy mechanism.

mTOR related models
The correct protein level is provided by the delicate balance between protein synthesis and breakdown.
High synaptic protein levels can occur as a result of high translation and/or accumulation of damaged
protein. In neurons, mTORC1 takes the role of braking autophagy. It is strategically positioned in the
presynaptic and postsynaptic regions. Under rich nutrient conditions, the target of mTORC1 is Unc-51-
like autophagy-activating kinase 1 (ULK-1) which phosphorylates in Ser757, the anti-autophagy region .
[70]
In this case, ULK-1 moves away from the AMP kinase (AMPK) and autophagy initiation is stopped. On
the contrary, in the starvation conditions, AMPK phosphorylates and activates ULK-1 in Ser317 which
mediates the phosphorylation and activation of Beclin-1 in Ser14, an important step in the “nucleation
phase” of autophagy . Beclin-1 promotes the lipidization of LC3-I to achieve the lipid form LC3-II which
[71]
[72]
enables membrane elongation and formation of autophagosomes . With lipidation, LC3-II is localized
to the phagophore membrane and mediates the formation of mature LC3-II autophagosomes, limiting
[73]
membrane elongation and cargo . Neuronal autophagy has a key role in protein balance and is an
important regulator of memory formation, synaptic plasticity, and structural remodeling [73,74] .

A possible scenario is that over-activated mTOR from hippocampal neurons from fragile X mice results
in decreased autophagy and accumulation of a particular group of synaptic proteins. Neurons from Fmr-1
knock-out mice showed the accumulation of ubiquitin-protein aggregates localized by p62, and autophagy
was impaired in Fmr-1 knock-out neurons. This findings in this study showed that autophagy and protein
degradation decreased in hippocampal neurons of this model. Excess mTOR activity is causally associated
with decreased autophagy causing spinal defects, impaired cognition, and exaggerated synaptic plasticity in
Fmr1- knock-out mice .
[75]