Schizophrenia
Reelin is a glycoprotein secreted by cajal retzius
cells to control cortical layering and by hippocampal GABAergic and cerebellar
glutaminergic granular cells in the adult brain to maintain neural networks.
There is significant downregulation of reelin expression in psychosis by
inducing recruitment of Akt and PI3K via phosphorylation of disrupted-in-schizophrenia
1 (DISC1) that regulate cell arrangement during the
development of the brain. Since, mTOR signalling cascade has not directly
involved in the development of cortical, but it has trophic effects on
hippocampal dendrite growth and branching by regulating expression of reelin
[8]. Moreover, BDNF induced activation of the mTOR signalling pathway and
involved in the cognitive process [9]. Therefore, any disruption in the
signalling of mTOR pathway either depressed or overactive has a significant
pathological role in psychosis or schizophrenia. The disrupted in schizophrenia
1 (DISC1) gene codes for a scaffolding protein which interacts with the various
cellular proteins to alter their functional activities at several stages of
neurodevelopment. Further, mTOR signalling is negatively regulated by DISC1,
where DISC1 knockdown mice possess abnormal morphology and excitability of
neuronal networks, deficits in aspects of cognition, depressive along with
anxiety-like behaviors of schizophrenia [10].
Learning
and memory
mTOR involved in the
neural functioning of CNS like learning and memory that achieved by long-term
synaptic plasticity (long term potentiation). A study on Aplysia and crayfish
and rat hippocampal slices demonstrate that treatment to rapamycin blocked long-term
synaptic plasticity and interfere with normal learning and memory functions.
Genetic ablation of mTOR inhibitors FKBP12 and S6K1 not completely mimic the
action of rapamycin [11]. mTORC1 also cause long term depression similar to
activation of metabotrophic glutamatergic receptor causing long term depression
(LTD) by increasing the level of MAP kinase and PI3- kinase-mTOR signalling and
protein synthesis synapse, consistent blocking mTOR signalling block the mGlu-R
dependent LTD [12]. mTORC2 control the actin cytoskeleton in non-neuronal cell
and play important role in regulating the neuronal process rapamycin treatment
reverse the behavioral phenotype of TSC1/2(Tuberous Sclerosis Complex (TSC)) mutant mice suggest that both
mTORC1and mTORC2 to regulate the synaptic physiology and behavior [13].
Epilepsy
As the mTOR signalling
regulates protein synthesis, synaptic plasticity decreases the pathological
abnormality occurs in epilepsy it can be hypothesized that mTOR also involved
in the mechanism of epileptogenesis in TSC patients. Inhibitors of mTOR
signalling have antiepileptogenic property that provides satisfactory treatment
of epilepsy. Treatment of rapamycin prevents the development of epilepsy and
other pathological and molecular changes that likely promote epileptogenesis.
In TSC models of epilepsy, seizure return within a week of rapamycin therapy
cessation which suggest that beneficial effect of rapamycin on seizure not
persist if rapamycin is stopped and the intermittent rapamycin treatment can
treat epileptogenesis [14].
Depression
Several studies reported
a decrease in the activation phosphorylated mTOR in animal model of
depression-like in chronic unpredictable stress (CUS) model of depression in
mice and rat shows a reduced level of phosphorylated mTOR and its downstream
signalling components such as Phosphor-P70S6K in prefrontal cortex hippocampus
and amygdala. Acute administration of ketamine increasing the brain-derived
neurotrophic factor and phosphorylated mTOR in hippocampus of rat and shows
antidepressants property in force swim test (FST). Some other modulators like
ascorbic acid, creatin, zinc, erythropoietin, scopolamine also shows
antidepressant property by increasing the amount of phosphorylated mTOR in the
brain [15,16].