mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus

Abstract

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 and Tsc2 mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 (Eker)-rats express social deficits similar to Tsc2 mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

A clinical update on tuberous sclerosis complex‐associated neuropsychiatric disorders (TAND)

“…Regarding brain abnormalities, tuber-brain proportion, cystic tubers and white matter abnormalities have been identified as possible risk markers for ASD (Numis et al, 2011). However, given the clearly complex and multi-componential pathophysiology of ASD, it is also important to be mindful that neither mutation status, structural abnormalities or seizures are necessary or sufficient to predict ASD in TSC (Curatolo et al, 2010; de Vries & Howe, 2007; Schneider, de Vries, Schonig, Rossner, & Waltereit, 2017; Waltereit, Japs, Schneider, de Vries, & Bartsch, 2011). …”

“…In spite of the theoretical value of mTOR inhibitors as treatment for ASD, most evidence to date is based on animal models (Schneider, de Vries, Schonig, Rossner, & Waltereit, 2017; Tsai et al, 2012; Waltereit, Japs, Schneider, de Vries, & Bartsch, 2011) or preliminary evidence in humans of a possible good response (Kilincaslan et al, 2017). A number of early-phase clinical trials are examining this question (www.clinicaltrials.gov), but no clinical recommendations about mTOR inhibitors for ASD in TSC can be made to date.…”

“…through structural brain abnormalities or seizures), de Vries & Howe proposed that there may also be a direct pathway from mTOR overactivation to TAND (de Vries & Howe, 2007; de Vries, 2010b). Encouraging murine work has supported the possibility that mTOR inhibition may reverse or improve aspects of TAND (Ehninger et al, 2008; Tsai et al, 2012; Waltereit et al, 2011), and have shown that there may be complex combinatorial pathways to TAND (Schneider et al, 2017; Waltereit et al, 2011). Very limited human data exist to date.…”

“…In spite of the theoretical value of mTOR inhibitors as treatment for ASD, most evidence to date is based on animal models (Schneider et al, 2017;Tsai et al, 2012;Waltereit et al, 2011) or preliminary evidence in humans of a possible good response (Kilincaslan et al, 2017). Gillberg, & Ahlsen, 1994;Hunt, 1993;Muzykewicz, Newberry, Danforth, Halpern, & Thiele, 2007) thus being 10 times more prevalent than in the general population (de Vries, 2010a).…”

A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex

“…[4][5][6] A positive effect of mTOR inhibitors on cognition and behavior in absence of epilepsy has been shown in animal models. [7][8][9][10] An open-label study examining sirolimus in TSC-associated lymphangioleiomyomatosis found recall memory improved in 7 of 8 patients. 11 A case series reported improved social interaction in 6 patients.…”