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 disorders [1][2][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 disability 2,4,5 . It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (e.g., mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis 1,2,4,6,7 . 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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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.

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.

The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that responds to proteostasis defects and stress conditions by tuning protein synthesis rates. While it has been long recognized that long-term memory formation requires new protein synthesis, our understanding of the central translational control mechanisms that regulate memory formation has advanced vastly. Indeed, novel causal and convergent evidence across different species and model systems shows that the ISR serves as a universal regulator of long-term memory formation. This chapter discusses the evidence explaining how inhibition of the ISR enhances long-term memory formation while activation of the ISR prevents it. In addition, it highlights the role of the ISR in different forms of long-lasting synaptic plasticity in the brain. Finally, the chapter addresses how dysregulated ISR signaling contributes to the pathogenesis of a wide range of cognitive and neurodegenerative disorders and discusses the future prospects for therapeutically targeting the ISR for the treatment of cognitive disorders.