Page 69 - AN-3-3

Advanced Neurology mTOR inhibition in epilepsy

and spinal syndrome caused by somatic PIK3CA variants; channel Kv1.1 and hyperpolarization of the action
27
megalencephaly polymicrogyria–polydactyly hydrocephalus potential threshold in an animal model, which led to
caused by germline AKT3 and PIK3R2 variants; Proteus hyperexcitability of CA1 pyramidal neurons. Hsieh et al.
28
37
syndrome caused by somatic AKT1 variants; Cowden concluded that mTOR-dependent ectopic expression of
29
syndrome and Bannayan–Riley–Ruvalcaba syndrome both the hyperpolarization-activated cyclic nucleotide-gated
caused by germline PTEN variants; 30,31 and TBC1D7-related potassium channel isoform 4 depolarizes dysmorphic
macrocephaly caused by germline TBC1D7 variants. 32 neurons and enhances their cAMP-dependent excitability,
contributing to seizure generation.
GATOR1 variants (DEPD5, NPRL2, and NPRL3)
also cause a unique clinical subset collectively known as Other proposed epileptogenic mechanisms in
GATORopathy or GATOR1-related epilepsy, distinct mTORopathies include abnormal dendritic spine
from tuberous sclerosis complex, other mTORopathies, morphology, disrupted glutamatergic synaptic transmission
or overgrowth syndromes. 16,33 The paradigmatic epilepsy or synaptic plasticity, dysregulated autophagy, astrogliosis,
phenotypes include familial focal epilepsy with variable and possible ectopic neurogenesis. 8,38,39 Moreover, there
foci and sleep-related hypermotor epilepsy. Baldassari is a complex interplay between the mTOR pathway and
et al. reported lesional and non-lesional focal epilepsy immune signaling. It has been shown that mTOR activation
33
in 38% and 62% of the patients with GATORopathy, is crucial for the early development of the central nervous
respectively. More than half of the patients with GATOR1- system’s immune system, the maturation, and function
related epilepsy were drug-resistant, 26% had intellectual of dendritic cells, T cell proliferation, as well as cytokine
disability, and 43% had neuropsychiatric comorbidities production and release. 8
such as oppositional disorder, attention deficit hyperactivity The precise mechanisms of epileptogenesis resulting
33
disorder, autism spectrum disorder, and mood disorder. from aberrant mTOR signaling networks are not yet fully
MCD was observed in 24% of the patients. Among those established and are thought to be multifactorial. Overall,
33
who underwent epilepsy surgery, 80% had a favorable it is believed that mTOR hyperactivation, in conjunction
surgical outcome with Engel score I–II. Emerging with heightened neuroinflammation, triggers a cascade of
33
evidence also suggests a higher risk of sudden unexpected downstream pathophysiological effects, including altered
death in epilepsy associated with GATOR1 variants, ion channel receptor expression, neurogenesis, apoptosis,
with an incidence of approximately 12% in a cohort exacerbated neuron damage, mossy fiber sprouting, and
(n=9/73), highlighting the need for more efficacious aberrant dendritic morphology. These changes lead to
treatments for GATOR1-related epilepsy. 16,33 Moloney neuronal hyperexcitability, altered synaptic transmission,
et al. recommended GATOR1 variant sequencing during increased seizure susceptibility, and, ultimately,
16
epilepsy surgery evaluation for all patients with either epileptogenesis. In addition, different pathogenic variants
8
lesional or non-lesional focal epilepsy, as the presence of a in the mTOR pathway exhibit different impacts on
GATOR1 variant may suggest an underlying occult MCD mTORC1 activation, leading to a range of phenotypes. 40
and also potentially predict a favorable surgical outcome.
5. Anti-seizure effects of mTOR inhibition in
4. Epileptogenesis animal models
In cases of mTOR hyperactivation, tau protein has been Meikle et al. demonstrated that effective pS6 reduction
41
found to be upregulated and abnormally phosphorylated, in the brain resulted in the restoration of Akt function,
which interferes with neuronal or glial growth and improvement in neurofilament abnormalities, myelination,
morphology, leading to altered cortical architecture. and cell size, as well as enhanced behavior, phenotype,
34
Dysplastic cytomegalic neurons observed in mTORopathies weight gain, and survival in Tsc1-ablated mice treated with
have been demonstrated to possess abnormal intrinsic rapamycin.
excitability, contributing to the generation and propagation mTOR inhibition has also shown anti-seizure and anti-
16
35
of epileptic discharge. On the other hand, Abs et al. epileptogenic effects in animal models of tuberous sclerosis
observed that acute biallelic deletion of the TSC1 gene in complex. Zeng et al. investigated the outcomes of early
42
healthy adult mice results in mTORC1 hyperactivation and late rapamycin treatment in mice with TSC1 gene
and neuronal hyperexcitability, without any evident inactivation, primarily in glia, which led to proliferation,
histopathological changes or structural brain pathologies, progressive epilepsy, and premature death. Late treatment
which is sufficient to induce seizures.
with rapamycin at 6 weeks of age suppressed seizures and
Sosanya et al. reported that elevated mTOR activity improved survival in mice already manifesting seizures,
36
induced repression of the voltage-gated potassium whereas early treatment at postnatal day 14, before the

Volume 3 Issue 3 (2024) 5 doi: 10.36922/an.3568