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Thus, non-human primate models may enable us to identify the pathogenesis that occurs in the human
brain but is hardly replicated in small animals.

The identification of neuronal loss in SHANK3 mutant monkeys also highlights the important function of
SHANK3 for neuronal survival during early brain development. It is highly likely that in primate brains,
SHANK3 is required for neuronal differentiation and maturation, such that the complete loss of SHANK3
would affect the survival of neurons. However, further studies are needed to pinpoint the mechanisms of
neuronal loss in SHANK3-deficient primates. On the other hand, partial deficiency in the expression or
function of SHANK3 due to heterozygous mutations or deficiency in some isoforms is more likely to affect
synaptic function and neuronal circuitry, leading to autistic phenotypes without neurodegeneration. Given
that the expression of SHANK3 is driven by multiple promoters to yield various isoforms, the use of non-
human primates would allow for investigating the relationship between neuronal loss and different
isoforms. Such studies would provide new insight into the function of SHANK3 and a better understanding
of how SHANK3 mutations alter behaviors to cause ASD.

It is important to note that in Zhao et al.’s report, only one SHANK3-targeted monkey exhibited almost
[51]
complete deletion of the SHANK3 gene and severe neuronal loss . The authors did not find any evidence
suggesting that the CRISPR/Cas9 targeting used in their study resulted in off-target events responsible for
such severe neurodegeneration. While the phenotypes observed in this unique SHANK3 mutant monkey
support the notion that complete loss of SHANK3 can lead to severe neuronal loss, further studies utilizing
additional SHANK3 mutant monkeys are necessary to validate this concept. Additionally, the neuronal loss
observed in the newborn SHANK3 mutant monkey could be attributed to neurodegeneration, impairment
of neurogenesis or neuronal differentiation, which warrants further investigation. A recent study
+/-
demonstrated that SHANK3 brain organoids are significantly smaller and contain fewer neurons
compared to wild-type controls . Thus, an alternative model for investigating the crucial role of SHANK3
[70]
in neuronal development could involve utilizing human brain organoids with CRISPR targeting SHANK3 .
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DECLARATIONS
Authors’ contributions
Wrote the first draft of the commentary: Zhang JW, He DJ
Edited and contributed to the final draft: Li XJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
This study was supported by the National Natural Science Foundation of China (81830032, 82071421,
82271902) and the Natural Science Foundation of Guangdong Province (2022A1515012651,
2022A1515012301).

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.