Cellular/Molecular
Hap1 Helps Tsc1 Inhibit mTORC1
Luis A. Mejia, Nadia Litterman, Yoshiho Ikeuchi, Luis de la Torre-Ubieta, Eric J. Bennett, et al.
(see pages 18015–18021)
The neurodevelopmental disorder tuberous sclerosis complex (TSC) is characterized not only by the presence of abnormal tuber-like growths in the brain, but also by intellectual disability, autism spectrum disorder, and epilepsy. The disease is caused by mutations in the proteins Tsc1 and Tsc2, which normally inhibit the mTORC1 signaling pathway and thus prevent excessive protein synthesis in response to extracellular signals. Using interaction proteomics analyses, Mejia et al. discovered that huntingtin-associated protein 1 (Hap1) directly binds to Tsc1 in neurons and participates in the inhibition of mTORC1 signaling. Knocking down Hap1 or Tsc1 in vitro caused hippocampal neurons to form multiple axons. Knockdown in vivo also disrupted migration of pyramidal neurons to the proper layer in the hippocampus. Inhibiting mTORC1 with the exogenous inhibitor rapamycin rescued the effects of Hap1 knockdown in vitro.
Knocking down Hap1 in hippocampal cultures caused formation of multiple axons (arrows). See the article by Mejia et al. for details.
Development/Plasticity/Repair
Gpr126 Is Necessary for Axon Myelination
Amit Mogha, Andrew E. Benesh, Chinmoy Patra, Felix B. Engel, Torsten Schöneberg, et al.
(see pages 17976–17985)
During development of the peripheral nervous system, immature Schwann cells migrate along bundles of growing axons and extend processes into the bundles to separate individual axons. Such interactions with axons are required to trigger Schwann cell maturation, which enables them to form myelin. Mice lacking the adhesion G-protein-coupled receptor Gpr126 lack myelin, suggesting that this protein is required at some stage of myelination. But because Gpr126-null mice die before birth (likely as a result of abnormal heart development), the role of Gpr126 in myelination has not been fully explored. Therefore, Mogha et al. restricted knockout of Gpr126 to Schwann cells. Although more Schwann cells were present in mutant nerves than in controls, axon sorting was delayed in mutants, and myelination did not occur. These phenotypes were partially rescued by activating adenylase cyclase in Schwann cells or treating nerves with a cAMP analog. Further experiments in cell lines indicated that Gpr126 increases cAMP levels, but couples to Gi as well as Gs proteins.
Systems/Circuits
The Amygdala Encodes Neutral Cues
Rotem Genud-Gabai, Oded Klavir, and Rony Paz
(see pages 17986–17994)
To function in the world while avoiding injury, animals must learn not only to identify cues that predict danger, but also to discriminate between danger cues and similar, innocuous cues. The amygdala has a central role in learning about cues that predict reward or danger, but Genud-Gabai et al. now show that neurons in this structure also respond to cues that have not been linked with any unconditioned stimulus. Similar numbers of neurons in macaque basolateral amygdala (BLA) acquired responses (increased or decreased activity) to cues paired with an aversive stimulus, cues of the same modality (auditory or visual) that were not paired with an unconditioned stimulus, and unpaired cues of a different modality. The magnitude of the acquired response was also similar for danger and neutral cues. Most neurons that responded to neutral cues stopped responding after the cues were paired with the aversive stimulus, suggesting separate populations of BLA neurons encode neutral and aversive cues.
Neurobiology of Disease
LGI1 Autoantibodies Are Tightly Linked to Limbic Encephalitis
Toshika Ohkawa, Yuko Fukata, Miwako Yamasaki, Taisuke Miyazaki, Norihiko Yokoi, et al.
(see pages 18161–18174)
Mutations in the secreted protein LGI1 cause lateral temporal lobe epilepsy, and autoantibodies against LGI1 are present in people with limbic encephalitis (LE), characterized partly by seizures. LGI1 interacts with multiple proteins and influences several neuronal processes; perhaps most relevant to seizure susceptibility, it prevents inactivation of voltage-gated potassium channels, and through interactions with ADAM22 and ADAM23, it promotes synapse formation and glutamate receptor expression. Having screened serum from patients with various immune-mediated neurological disorders, Ohkawa et al. found that ∼90% of people with LE had autoantibodies only against LGI1. Serum from these patients reduced interactions between LGI1 and ADAM22 and ADAM23, whereas LGI1 autoantibodies from patients without LE did not. Furthermore, serum from LE patients reduced synaptic AMPA receptor clusters in rat hippocampal neurons, as did incubating neurons with an ADAM22 fragment that disrupts LGI1–ADAM22 interactions. Moreover, expression of AMPARs, ADAM22, and ADAM23 were lower in the dentate gyrus of LGI1-null mice than in controls. Together, the data suggest that LGI1 autoantibodies lead to seizures by disrupting interactions between LGI1 and ADAM22 and ADAM23, and thus reducing synaptic expression of AMPARs.
