Over-production of Tau proteins has been demonstrated to cause hyperexcitability
(see The Role of Microtubules in Epilepsy). The activation of mTOR increases Tau production
(Caccamo et al., 2013;
Tang et al., 2013;
Tang et al., 2015).
Therefore, hyperactive mTOR may promote epilepsy by enhancing excitability. This novel mechanism is supported by the following observations.
- Mutations in tuberous sclerosis complex (TSC1 or TSC2) result in Tau up-regulation and epilepsy
(Sarnat and Flores-Sarnat, 2015). TSC1 and TSC2 are the crucial negative regulators of mTOR.
Their loss of function may activate mTOR, leading to seizures (Uhlmann et al., 2002).
- Mutations in the PI3K/AKT/mTOR pathway cause epilepsy-associated diseases
(Lee et al., 2012;
Poduri et al., 2012;
Jansen et al., 2015).
- PTEN (phosphatase and tensin homolog on chromosome ten) can inhibit the PI3K/AKT/mTOR pathway.
Mutations in PTEN promote mTOR activation, thereby leading to epilepsy (Garcia et al., 2014).
- DISC1 (Disrupted-In-Schizophrenia 1) is another negative regulator for mTOR signaling
(Kim et al., 2009). Its knockdown results in hyperexcitability
(Zhou et al., 2013).
- mTOR is also negatively regulated by the GATOR1 complex (composed of DEPDC5, NPRL2 and NPRL3)
(Bar-Peled et al., 2013).
Mutations in GATOR1 cause focal epilepsy and cortical dysplasia (Baulac et al., 2015;
Sim et al., 2015;
Ricos et al., 2015).
- Vitamin D is an mTOR inhibitor (Lisse and Hewison, 2011).
Its deficiency is highly prevalent in epilepsy patients (Jiang et al., 2015).
- Peroxisome proliferator-activated receptor γ (PPAR-γ) is a transcription factor that suppresses mTOR expression
(Vasheghani et al., 2015;
Dell'Accio and Sherwood, 2015) and increases PTEN expression
(Farrow and Evers, 2003).
Pioglitazone, a PPAR-γ agonist, has been demonstrated to protect rats from status epilepticus by inhibiting the mTOR signaling pathway
(San et al., 2015).
- While hyperexcitability could arise from alteration at synapses, mTOR hyperactivation is not always associated with enhanced synaptic transmission
(Lasarge and Danzer, 2014;
Wang et al., 2015). Furthermore, mTOR-dependent epilepsy caused by acute biallelic Tsc1 deletion
is not accompanied by any obvious histological changes (Abs et al., 2013).
- Acute kainate treatment in rats induces a biphasic activation of mTOR (Zeng et al., 2009).
The second phase of mTOR activation correlates with the increase of Tau proteins (Pollard et al., 1994),
which may set the stage for later spontaneous recurrent seizures (epilepsy).
- The mTOR-induced hyperexcitability is likely to originate from persistent Na+ current, INaP
(Manuel and Heckman, 2011;
Carunchio et al., 2010).
The major source of INaP is the ionic current through non-inactivating Na+ channel, Nav1.6, which can be regulated by microtubules
and Tau proteins at the axon initial segment (see Differential Effects of 3 and 4 Repeat Tau on Excitability).
Author: Frank Lee
First published: December 9, 2015
Last updated: December 25, 2015