Neuroscience
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L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. ⋯ In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence.
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We previously characterized the organization of presympathetic-premotor neurons (PSPMNs), which send descending poly-synaptic projections with collaterals to skeletal muscle and the adrenal gland. Such neurons may play a role in shaping integrated adaptive responses, and many of them were found within well-characterized regions of noradrenergic cell populations suggesting that some of the PSPMNs are catecholaminergic. To address this issue, we used retrograde trans-synaptic tract-tracing with attenuated pseudorabies virus (PRV) recombinants combined with multi-label immunofluorescence to identify PSPMNs expressing tyrosine hydroxylase (TH). ⋯ Within SubC and the A7 cell group, about 70% of TH-ir neurons were PSPMNs, which was a significantly greater fraction of neurons than in the other brain regions we examined. These findings indicate that TH-ir neurons near the pontomesencephalic junction that are distributed across the LC, SubC, and the A7 may play a prominent role in somatomotor-sympathetic integration, and that the major functional role of the A7 and SubC noradrenergic cell groups maybe in the coordination of concomitant activation of somatomotor and sympathetic outflows. These neurons may participate in mediating homeostatic adaptations that require simultaneous activation of sympathetic and somatomotor nerves in the periphery.
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17β-Estradiol (E2) crucially affects several processes in the hippocampus of both sexes. E2 acts upon estradiol receptors ERα and ERβ, influencing target gene expression and/or modulates intracellular signaling cascades. Another potent modulator of hippocampal function is nucleoside adenosine, the final product of ectonucleotidase cascade, enzymes which hydrolyze extracellular ATP to adenosine. ⋯ Selective ERα receptor agonist, PPT, induced upregulation of both the protein level and activity of eN, while application of selective ERβ receptor agonist, DPN, increased only the activity of eN. In both cases, E2 entered into the intracellular compartment and activated ER(s), which was demonstrated by membrane impermeable E2-BSA conjugate. Together these results imply that E2-induced effects on connectivity and functional properties of the hippocampal synapses may be in part mediated through observed effect on eN.
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Structural plasticity of dendritic spines, which underlies higher brain functions including learning and memory, is dynamically regulated by the actin cytoskeleton and its associated proteins. Drebrin A is an F-actin-binding protein preferentially expressed in the brain and localized in the dendritic spines of mature neurons. Isoform conversion from drebrin E to drebrin A and accumulation of the latter in dendritic spines occurs during synapse maturation. ⋯ In parallel with this age-dependent impairment, DAKO mice exhibited impaired hippocampus-dependent fear learning in an age-dependent manner; the impairment was evident in adult mice, but not in adolescents. In addition, histological investigation revealed that the spine length of the apical dendrite of CA1 pyramidal cells was significantly longer in adult DAKO mice than in wild-type mice. Our data indicate that the roles of drebrin E and drebrin A in brain function are different from each other, that the isoform conversion of drebrin is critical, and that drebrin A is indispensable for normal synaptic plasticity and hippocampus-dependent fear memory in the adult brain.
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Motor, sensory, and autonomic abnormalities are reported for toll-like receptor 9 (TLR9) knock-out (KO) mice. However, a physiological role of TLR9 in the nervous system is largely unknown. Since altered synaptic transmission can contribute to sensory and motor abnormalities, we evaluated neuromuscular junction (NMJ) function and morphology of TLR9 KO mice. ⋯ This alteration may result from ACh-induced decline of acetylcholine receptor (AChR) expression resulting from increased frequency and amplitude of mEPCs. At the same time, excessive spontaneous vesicular ACh release may initiate retrograde suppression of excitation-secretion coupling. These data suggest a novel role of TLR9 in the development of the NMJ.