Highlights d Treatment with L. reuteri rescues social deficits in several ASD mouse models d L. reuteri reverses social deficits via the vagus nerve d L. reuteri reverses social deficits even in germ-free mice d OXTR inhibition prevents L. reuteri's effects on social behavior and VTA plasticity

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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:

In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network models.

Spike-timing-dependent plasticity (STDP) is a form of long-term synaptic plasticity exploiting the time relationship between postsynaptic action potentials (APs) and EPSPs. Surprisingly enough, very little was known about STDP in the cerebellum, although it is thought to play a critical role for learning appropriate timing of actions. We speculated that low-frequency oscillations observed in the granular layer may provide a reference for repetitive EPSP/AP phase coupling. Here we show that EPSP-spike pairing at 6

BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca 2+ sensitivity, voltage dependence and gating properties. Abundantly expressed in the CNS, they have the peculiar characteristic of being activated by both voltage and intracellular calcium rise. The increase in intracellular calcium via voltage-dependent calcium channels (Ca v ) during spiking triggers conformational changes and BK channel opening. This narrows the action potential and Marilena Griguoli received her PhD degree at the International School for Advanced Studies in Trieste. After a Post-doc at the Interdisciplinary Institute for Neuroscience in Bordeaux in the lab of C. Mulle, she joined EBRI as a senior scientist. Her research is focused on cholinergic regulation of the hippocampal circuits in vivo using electrophysiology combined with opto/chemogenetic tools. Martina Sgritta received her PhD in Biomedical Science at the University of Pavia. She then moved as a Post-doc to EBRI in Rome, where she is studying with electrophysiological tools synaptic plasticity in an animal model of autism. Enrico Cherubini trained as a child neurologist and is full professor of physiology at the International School for Advanced Studies in Trieste. Recently he moved to EBRI in Rome as a scientific director. His research interest focuses on the molecular and cellular mechanisms regulating synaptic plasticity processes particularly during postnatal development. induces a fast after-hyperpolarization that shuts calcium channels. The tight coupling between BK and Ca v channels at presynaptic active zones makes them particularly suitable for regulating calcium entry and neurotransmitter release. While in most synapses, BK channels exert a negative control on transmitter release under basal conditions, in others they do so only under pathological conditions, serving as an emergency brake to protect against hyperactivity. In particular cases, by interacting with other channels (i.e. limiting the activation of the delayed rectifier and the inactivation of Na + channels), BK channels induce spike shortening, increase in firing rate and transmitter release. Changes in transmitter release following BK channel dysfunction have been implicated in several neurological disorders including epilepsy, schizophrenia, fragile X syndrome, mental retardation and autism. In particular, two mutations, one in the α and one in the β3 subunit, resulting in a gain of function have been associated with epilepsy. Hence, these discoveries have allowed identification of BK channels as new drug targets for therapeutic intervention. Abstract figure legend BK channels control transmitter release. A, BK channels tightly coupled with Ca v contribute to the repolarizing phase of the action potential, spike width and transmitter release. B, loss of BK channels induced by genetic deletion causes, as in the presence of selective blockers, action potential broadening and increase in t...

Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1—an mRNA whose translation is controlled by p-eIF2α—in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.DOI: http://dx.doi.org/10.7554/eLife.17517.001

Climbing fibers (CFs) originating in the inferior olive (IO) constitute one of the main inputs to the cerebellum. In the mammalian cerebellar cortex each of them climbs into the dendritic tree of up to 10 Purkinje cells (PCs) where they make hundreds of synaptic contacts and elicit the so-called all-or-none complex spikes controlling the output. While it has been proven that CFs contact molecular layer interneurons (MLIs) via spillover mechanisms, it remains to be elucidated to what extent CFs contact the main type of interneuron in the granular layer, i.e., the Golgi cells (GoCs). This issue is particularly relevant, because direct contacts would imply that CFs can also control computations at the input stage of the cerebellar cortical network. Here, we performed a systematic morphological investigation of labeled CFs and GoCs at the light microscopic level following their path and localization through the neuropil in both the granular and molecular layer. Whereas in the molecular layer the appositions of CFs to PCs and MLIs were prominent and numerous, those to cell-bodies and dendrites of GoCs in both the granular layer and molecular layer were virtually absent. Our results argue against the functional significance of direct synaptic contacts between CFs and interneurons at the input stage, but support those at the output stage.