Mutations in the AASS ( Aminoadipate-Semialdehyde Synthase ) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurological disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal developm...

Regeneration can occur in peripheral neurons after injury, but the mechanisms involved are not fully delineated. Macrophages in dorsal root ganglia (DRGs) are involved in the enhanced regeneration that occurs after a conditioning lesion (CL), but how macrophages stimulate this response is not known. Oncomodulin (Ocm) has been proposed as a proregenerative molecule secreted by macrophages and neutrophils, is expressed in the DRG after axotomy, and stimulates neurite outgrowth by DRG neurons in culture. Wild-type (WT) and Ocm knock-out (KO) mice were used to investigate whether Ocm plays a role in the CL response in DRG neurons after sciatic nerve transection. Neurite outgrowth was measured after 24 and 48 h in explant culture 7 d after a CL. Sciatic nerve regeneration was also measured in vivo 7 d after a CL and 2 d after a subsequent sciatic nerve crush. The magnitude of the increased neurite outgrowth following a CL was significantly smaller in explants from Ocm KO mice than in explants from WT mice. In v...

SIPA1L1 (also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the PSD-95/NMDA-R-complex. However, its physiological role remains poorly understood. Here, we performed expression analyses using super-resolution microscopy in mouse brain and demonstrated that SIPA1L1 is mainly localized to general submembranous regions in neurons, but surprisingly, not to PSD. Our screening for physiological interactors of SIPA1L1 in mouse brain identified spinophilin and neurabin-1, regulators of GPCR signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1 -/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1 -/- mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation, and striking behavioral anomalies, such...

A key goal of consciousness science is identifying neural signatures of being aware vs. unaware of simple stimuli. This is often investigated in the context of near-threshold detection, with reports of stimulus awareness being linked to heightened activation in a frontoparietal network. However, due to reports of stimulus presence typically being associated with higher confidence than reports of stimulus absence, these results could be explained by frontoparietal regions encoding stimulus visibility, decision confidence or both. In an exploratory analysis, we leverage fMRI data from 35 human participants (20 females) to disentangle these possibilities. We first show that, whereas stimulus identity was best decoded from the visual cortex, stimulus visibility (presence vs. absence) was best decoded from prefrontal regions. To control for effects of confidence, we then selectively sampled trials prior to decoding to equalize confidence distributions between absence and presence responses. This analysis reveal...

Tuberous sclerosis complex (TSC) is caused by mutations in Tsc1 or Tsc2 , whose gene products inhibit the small G-protein Rheb1. Rheb1 activates mTORC1, which may cause refractory epilepsy, intellectual disability and autism. The mTORC1 inhibitors have been used for TSC patients with intractable epilepsy. However, its effectiveness for cognitive symptoms remains unclear. We found a new signaling pathway for synapse formation through Rheb1 activation, but not mTORC1. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib increased unfarnesylated (inactive) Rheb1 levels and restored synaptic abnormalities in cultured Tsc2+/- neurons, whereas rapamycin did not enhance spine synapse formation. Lonafarnib treatment also restored the plasticity-related Arc expression in cultured Tsc2+/- neurons. Lonafarnib action was partly dependent on the Rheb1 reduction with syntenin. Oral administration of lonafarnib increased unfarnesylated protein levels without affecting mTORC1and MAP kinase signal...

Axon guidance receptors such as DCC contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in DCC have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic Dcc mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of Dcc heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the Dcc+/- motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult Dcc+/- mice during treadmill locomotion, except for a decreased occurrence of out-o...

G-protein-coupled receptors (GPCRs) coupled to Gi signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile) in shaping the emergence of adult anxiodepressive behaviors and sensorimotor gating. To address the role of Gi signaling in these developmental windows, we used a CaMKIIα-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD (designer receptor exclusively activated by designer drugs) in forebrain excitatory neurons and enhanced Gi signaling via chronic administration of the DREADD agonist, clozapine- N -oxide (CNO) in the postnatal window (postnatal days 2–14) or the juvenile window (postnatal days 28–40). We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CaMKII-positive neurons in the forebrain, and that the administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in expr...

We previously reported that ADAM17 is a key protease regulating myelin formation. We now describe a role for ADAM17 during the Wallerian degeneration process. Unexpectedly, we observed that glial ADAM17, by regulating p75NTR processing, cell autonomously promotes remyelination, while neuronal ADAM17 is dispensable. Accordingly, p75NTR abnormally accumulates specifically when ADAM17 is maximally expressed leading to a down–regulation of tPA expression, excessive fibrin accumulation over time and delayed remyelination. Mutant mice also present impaired macrophage recruitment and defective nerve conduction velocity. Thus, ADAM17 expressed in Schwann cells, controls the whole Wallerian degeneration process and its absence hampers effective nerve repair. Collectively, we describe a previously uncharacterized role for glial ADAM17 during nerve regeneration. Based on the results of our study, we posit that, unlike development, glial ADAM17 promotes remyelination through the regulation of p75NTR –mediated fibrinol...

Chemical communication controls a wide range of behaviors via conserved signaling networks. Axon regeneration in response to injury is determined by the interaction between the extracellular environment and intrinsic growth potential. In this study, we investigated the role of chemical signaling in axon regeneration in Caenorhabditis elegans . We find that the enzymes involved in ascaroside pheromone biosynthesis, ACOX-1.1, ACOX-1.2, and DAF-22, participate in axon regeneration by producing a dauer-inducing ascaroside, ascr#5. We demonstrate that the chemoreceptor genes, srg-36 and srg-37 , which encode G-protein-coupled receptors for ascr#5, are required for adult-specific axon regeneration. Furthermore, the activating mutation in egl-30 encoding Gqα suppresses axon regeneration defective phenotype in acox-1.1 and srg-36 srg-37 mutants. Therefore, the ascaroside signaling system provides a unique example of a signaling molecule that regulates the regenerative pathway in the nervous system. SIGNIFICANCE S...

Patricia L. Murphy, Jesse Isaacman-Beck, and Michael Granato (see pages [762–776][1]) Unlike CNS axons, peripheral nerves can regenerate and reinnervate their targets after injury. This requires axons to navigate through an environment that has changed substantially since the axons' initial