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Page 258 Dana et al. J Transl Genet Genom 2020;4:251-62 I http://dx.doi.org/10.20517/jtgg.2020.25

plays a role in the transcriptional regulation o both dopamine and serotonin receptors in the brain.
All studies have shown that CC2D1A regulated critical pathways for cognitive functions with neuronal
differentiation [102,103] . Although there are not many studies in this animal model, abnormalities were found
in the brain in the studies performed. Developmental changes in neurons of Cc2d1a knockout mouse
brains were demonstrated during synapse maturation and induced neurotransmitter release. Based on these
[100]
findings, it is thought that the CC2D1A gene serves as a developmental regulator of synapse function .
CC2D1A knock-out or knock-down in vitro experiments showed a decrease in hippocampal neurons.
Also, delays in synaptic maturation have been observed in cortical neurons. In these animal models, it has
been determined that there is a lack of neuronal plasticity, spatial learning, and memory accompanying
decreased socialization, hyperactivity, anxiety, and excessive self-care [101] and Cc2d1a has been shown to
control synaptic maturation of excitatory neurons [100] . Further studies are needed to determine whether
CC2D1A controls sex-specific circuit function. Conditional removal of CC2D1A from the dorsal raphe
demonstrated increased anxiety and depression-like behavioral phenotypes which correlated with reduced
serotonin levels and increased 5HT-1A autoreceptor in the raphe, in both males and females [103] , suggesting
that there may be regional specificity in the function of CC2D1A.

In vitro studies in hippocampal neurons and embryonic fibroblasts from CC2D1A knock-out mice showed
[105]
that CC2D1A binds to phosphodiesterase 4D (PDE4D), an enzyme involved in cAMP degradation . In
a recent study, PDE4D activation and downstream signaling molecules were tested in the hippocampus
of Cc2d1a knock-out mice. Cc2d1a knock-out male mice were hyperactive and show a deficit in spatial
memory, which led to a reduction in cAMP response element-binding protein signaling but this finding has
not been correlated with female mice. These findings showed that CC2D1A regulates cAMP intracellular
signaling in the male-specific regions of the hippocampus [106] . In our recent study, we showed the
dysregulation of autophagy with CC2D1A deficient mice in the hippocampus. We wanted to evaluate the
severity of autism by creating two different groups and followed them over the next three generations. LC3
and Beclin gene and protein expression levels in the hippocampus tissues of male and female mice in both
groups were examined. All of the animal groups were observed to be extremely aggressive and hyperactive.
Overall decreases were observed in autophagy levels. In the literature, this was the first major study in the
[48]
CC2D1A mouse model in which autism was associated with autophagy .

CONCLUSION
Genetic studies of autism have made surprising progress over the past 20 years. Our understanding of
the genetic and epigenetic factors in ASD etiology and the interaction on the disease will be continued to
improve with future studies and ongoing research results.

Animal models are used to study potential disorder mechanisms. The well-known causes of autism are
commonly based on specific human genetic mutations; however, ASD pathogenesis is most likely shaped
by a complex interaction between several genetic variants as well as environmental factors in humans. In
the animal models, monogenic mutations can lead to milder phenotypes that might explain some of the
differences observed in behavioral manifestations between ASD patients and animal models. Given the
clinical heterogeneity of the ASD patients, it is controversial whether it is necessary or even possible to see
all the human symptoms in rodent models. However, monogenic rodent models are a valuable resource
for solving the cause-and-effect relationships of ASD since the majority of susceptibility genes appear to
converge in shared biological pathways. Therefore, rodent models are important preclinical tools necessary
to investigate the validation of pathophysiology, gene function, and therapeutic approaches in ASD [107] .

Choosing the right model is of great importance for ASD studies and progress will be made in the
reflection of the results to be obtained in the clinic. Especially, the studies to be done with CC2D1A models
are expected to gain new information in this field.