Targeted suppression of mTORC2 reduces seizures across models of epilepsy.

Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models of epilepsy. Finally, we identify a target of mTORC2, Nav1.2, which has been implicated in epilepsy and neuronal excitability. Our findings, which are generalizable to several models of human seizures, raise the possibility that inhibition of mTORC2 may serve as a broader therapeutic strategy against epilepsy.

Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency.

Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders1-3. Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability2,4,5. It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis1,2,4,6,7. Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.

A causal inference explanation for enhancement of multisensory integration by co-articulation.

The McGurk effect is a popular assay of multisensory integration in which participants report the illusory percept of "da" when presented with incongruent auditory "ba" and visual "ga" (AbaVga). While the original publication describing the effect found that 98% of participants perceived it, later studies reported much lower prevalence, ranging from 17% to 81%. Understanding the source of this variability is important for interpreting the panoply of studies that examine McGurk prevalence between groups, including clinical populations such as individuals with autism or schizophrenia. The original publication used stimuli consisting of multiple repetitions of a co-articulated syllable (three repetitions, AgagaVbaba). Later studies used stimuli without repetition or co-articulation (AbaVga) and used congruent syllables from the same talker as a control. In three experiments, we tested how stimulus repetition, co-articulation, and talker repetition affect McGurk prevalence. Repetition with co-articulation increased prevalence by 20%, while repetition without co-articulation and talker repetition had no effect. A fourth experiment compared the effect of the on-line testing used in the first three experiments with the in-person testing used in the original publication; no differences were observed. We interpret our results in the framework of causal inference: co-articulation increases the evidence that auditory and visual speech tokens arise from the same talker, increasing tolerance for content disparity and likelihood of integration. The results provide a principled explanation for how co-articulation aids multisensory integration and can explain the high prevalence of the McGurk effect in the initial publication.

mTORC2, but not mTORC1, is required for hippocampal mGluR-LTD and associated behaviors.

The mechanistic target of rapamycin complex 1 (mTORC1) has been reported to be necessary for metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD). Here we found that mTORC1-deficient mice exhibit normal hippocampal mGluR-LTD and associated behaviors. Moreover, rapamycin blocks mGluR-LTD in mTORC1-deficient mice. However, both rapamycin and mGluR activation regulate mTOR complex 2 (mTORC2) activity, and mTORC2-deficient mice show impaired mGluR-LTD and associated behaviors. Thus, mTORC2 is a major regulator of mGluR-LTD.