The Journal of neuroscience : the official journal of the Society for Neuroscience
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Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits. ⋯ Using transcranial in vivo multiphoton microscopy, we find that fmr1 KO mice have similar spine density but increased dendritic spine turnover compared with WT mice. Finally, we report that motor skill training-induced formation of dendritic spines is impaired in fmr1 KO mice. We conclude that FMRP plays a role in motor skill learning and that reduced functional and structural synaptic plasticity might underlie the behavioral deficit in the fmr1 KO mouse.
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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. ⋯ Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS.
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erbb4 is a susceptibility gene for schizophrenia and ErbB4 signals have been hypothesized to function in a number of cortical developmental processes (Silberberg et al., 2006; Mei and Xiong, 2008). Several recent studies show that the expression of ErbB4 is mainly restricted to GABAergic interneurons (Yau et al., 2003; Woo et al., 2007), specifically, to parvalbumin-positive (PV) fast-spiking (FS) interneurons (Vullhorst et al., 2009; Fazzari et al., 2010), a large majority of which are PV FS basket cells (Kawaguchi, 1995; Taniguchi et al., 2013). However, in the medial prefrontal cortex (mPFC), a brain region that is closely associated with neuropsychiatric disorders including schizophrenia, little is known about the roles of ErbB4 signals during the development of GABAergic circuitry particularly that associated with PV FS basket cells. ⋯ Interestingly, they were required for the final maturation rather than the initial formation of glutamatergic synapses on PV FS basket cells. Furthermore, activity-dependent GABAergic PV FS pyramidal neuron transmission was decreased, whereas activity of pyramidal neurons was increased in KO mice. Together, these data indicate that ErbB4 signals contribute to the development of GABAergic circuitry associated with FS basket cells in component- and stage-dependent manners in the mPFC in vivo, and may suggest a mechanism for neuropsychiatric disorders including schizophrenia.
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Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. ⋯ Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.
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Axonal degeneration occurs in multiple neurodegenerative disorders of the central and peripheral nervous system. Although the underlying molecular pathways leading to axonal degeneration are incompletely understood, accumulating evidence suggests contributions of impaired mitochondrial function, disrupted axonal transport, and/or dysfunctional intracellular Ca(2+)-homeostasis in the injurious cascade associated with axonal degeneration. Utilizing an in vitro model of axonal degeneration, we studied a subset of mouse peripheral sensory neurons in which neurites were exposed selectively to conditions associated with the pathogenesis of axonal neuropathies in vivo. ⋯ Pharmacological inhibition of the Na(+)/K(+)-ATPase with ouabain induced neurite degeneration, which was attenuated by TTX and KB-R7943, supporting a contribution of sodium channels in axonal degenerative pathways accompanying impaired Na(+)/K(+)-ATPase activity. Conversely, oxidant stress (H2O2)-induced neurite degeneration was not attenuated by TTX. Our results demonstrate that both energetic and oxidative stress targeted selectively to neurites induces neurite degeneration and that blockade of sodium channels and of reverse NCX activity blockade partially protects neurites from injury due to energetic stress, but not from oxidative stress induced by H2O2.