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Advanced Neurology Role of immunosuppressants in autism

Figure 1. Role of mTOR in ASD pathogenesis. Mammalian target of rapamycin (mTOR) is divided into two parts, mTORC1 and mTORC2, with molecules
containing MLST8, DEPTOR, TTI1, and TEL2. mTORC1 activates mRNA, S6K1, and 4EBP1/2, finally leading to autism. Upregulation of PI3K-AKT/
mTOR signaling in the progression of autism. PI3K is activated by the receptor tyrosine kinase receptor. Activation of PI3K phosphorylates and converts
phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3), leading to AKT activation. AKT signaling cascade
inhibits the TSC1/2 complex by removing its inhibition from mTORC1. Mutation in PTEN and TSC1/2 causes mTORC1 hyperactivation. Elevation of
cytokines causes activation of receptor, which leads to elevation of mTORC1. This leads to abnormal mRNA translation as well as EI imbalance; this all
leads to autistic-like symptoms.
Abbreviations: PI3K: Phosphoinositide-3-kinase; PIP2: Phosphatidylinositol (4,5) biphosphate; PIP3: Phosphatidylinositol (3,4,5) triphosphate; TSC1/2:
Tuberous sclerosis complex 1; mTOR: Mammalian target of rapamycin; PTEN: Phosphatase and TENsin homolog deleted on chromosome 10; IFN:
Interferons; NK cells: Natural killer cells; AKT: AK strain transforming; EI: Electrolyte imbalance.

in males with ASD using RNA sequencing; however, none with major depressive disorder. Dysregulation of the
of the genes are individually differently expressed. These mTOR/p70S6K/eIF4B pathway has been linked to a wide
results showed that there is significant variation in mTOR range of pathologies, including encephalopathy, dendritic
expression and signaling in idiopathic ASD . spine abnormalities, and even malignancy (Figure 2).
[37]
Environmental stress elevates mTOR signaling and plays
A mouse mutant strain in which telencephalic vesicles
could not form due to diminished proliferation provided a major role in the emergence of autistic symptoms. One
of the best-characterized environmental exposures that
evidence that the mTOR pathway is a crucial positive raises the risk of ASD is maternal illness or immunological
regulator of cell survival and proliferation. When a activation during pregnancy . Animal models of epilepsy
[33]
constitutively active form of mTOR was induced from show a similar rapid response in mTOR activity. In
the Emx1 promoter in early neuroprogenitors, the cells addition, treating an animal model of neonatal convulsions
died and the brain shrank. Megalencephaly with neuronal with rapamycin may inhibit the emergence of behavioral
hypertrophy was observed in mice with post-mitotic impairments in the offspring [41,42] .
expression of constitutively active mTOR. There is an
increase in proliferation and megalencephaly when Tsc1 2.1.1. mTOR in different cell types involved in ASD
is conditionally deleted using the Emx1-Cre driver [38,39] . mTOR signaling has been implicated in several cell types in
According to these findings, mTORC1 hyperactivation the brain that are thought to be relevant to the pathogenesis
during fetal brain development may result in increased of ASD. These include:
neural stem cells (NSC) and neural progenitor proliferation,
neuronal production, and bloated head and brain size. Neurons. mTOR signaling has been shown to play
a critical role in neuronal development and synaptic
Conversely, mTORC1 inhibition results in fewer plasticity, which are disrupted in ASD. Hyperactivation of
differentiated neurons and microcephaly. Regulatory mTOR signaling has been observed in some ASD animal
phosphorylation in the downstream signaling pathway has models and post-mortem human brain tissue, and is
[40]
been investigated by Jernigan et al. The proteins mTOR, thought to contribute to the aberrant neuronal growth and
p70S6K, and eIF4B were all found to be reduced in people connectivity observed in ASD [30,43] .

Volume 2 Issue 2 (2023) 4 https://doi.org/10.36922/an.391