Summary The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses.
Plotkin JL, Shen W, Rafalovich I, Sebel LE, Day M, Chan CS, Surmeier DJ. Regulation of dendritic calcium release in striatal spiny projection neurons. J Neurophysiol 110: 2325-2336, 2013. First published August 21, 2013 doi:10.1152/jn.00422.2013.-The induction of corticostriatal long-term depression (LTD) in striatal spiny projection neurons (SPNs) requires coactivation of group I metabotropic glutamate receptors (mGluRs) and L-type Ca 2ϩ channels. This combination leads to the postsynaptic production of endocannabinoids that act presynaptically to reduce glutamate release. Although the necessity of coactivation is agreed upon, why it is necessary in physiologically meaningful settings is not. The studies described here attempt to answer this question by using two-photon laser scanning microscopy and patch-clamp electrophysiology to interrogate the dendritic synapses of SPNs in ex vivo brain slices from transgenic mice. These experiments revealed that postsynaptic action potentials induce robust ryanodine receptor (RYR)-dependent Ca 2ϩ -inducedCa 2ϩ release (CICR) in SPN dendritic spines. Depolarization-induced opening of voltage-gated Ca 2ϩ channels was necessary for CICR. CICR was more robust in indirect pathway SPNs than in direct pathway SPNs, particularly in distal dendrites. Although it did not increase intracellular Ca 2ϩ concentration alone, group I mGluR activation enhanced CICR and slowed Ca 2ϩ clearance, extending the activity-evoked intraspine transient. The mGluR modulation of CICR was sensitive to antagonism of inositol trisphosphate receptors, RYRs, src kinase, and Ca v 1.3 L-type Ca 2ϩ channels. Uncaging glutamate at individual spines effectively activated mGluRs and facilitated CICR induced by back-propagating action potentials. Disrupting CICR by antagonizing RYRs prevented the induction of corticostriatal LTD with spike-timing protocols. In contrast, mGluRs had no effect on the induction of long-term potentiation. Taken together, these results make clearer how coactivation of mGluRs and L-type Ca 2ϩ channels promotes the induction of activity-dependent LTD in SPNs.two-photon imaging; calcium; long-term depression; plasticity; striatum
Mice carrying bacterial artificial chromosome (BAC) transgenes have become important tools for neuroscientists, providing a powerful means of dissecting complex neural circuits in the brain. Recently, it was reported that one popular line of these mice – mice possessing a BAC transgene with a D2 dopamine receptor (Drd2) promoter construct coupled to an enhanced green fluorescent protein (eGFP) reporter – had abnormal striatal gene expression, physiology and motor behavior. Unlike most of the work using BAC mice, this interesting study relied upon mice backcrossed on the outbred Swiss Webster strain that were homozygous for the Drd2-eGFP BAC transgene.The experiments reported here were conducted to determine whether mouse strain or zygosity was a factor in the reported abnormalities. As reported, SW mice were very sensitive to transgene expression. However, in more commonly used inbred strains of mice (C57BL/6, FVB/N) that were hemizygous for the transgene, the Drd2-eGFP BAC transgene did not alter striatal gene expression, physiology or motor behavior. Thus, the use of inbred strains of mice which are hemizygous for the Drd2 BAC transgene provide a reliable tool for studying basal ganglia function.
Response surface modeling of the potentiation of GABA responses (0.3-1,000 microm) by sevoflurane and propofol revealed that the two anesthetics modulated receptor function in an additive manner. These results are consistent with recent mutagenesis studies, suggesting that these two drugs have separate binding sites and converging pathways of action on the GABAA receptor.
Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics.
BACKGROUND: MicroRNAs (miRNAs), a group of non-coding post-transcriptional regulators of gene expression, are dysregulated in clear cell renal cell carcinoma (ccRCC) and play an important role in carcinogenesis. Our prior work identified a subset of miRNAs in pT1 ccRCC tumors associated with progression to metastatic disease. OBJECTIVE: To investigate the impact of two of these dysregulated miRNA, miR-15a-5p and -26a-5p, in an effort to elucidate the mechanisms underpinning aggressive forms of stage I ccRCC. METHODS: The ccRCC cell line 786-O was transfected with pre-miRs-15a-5p and -26a-5p to rescue expression. Cell proliferation was measured via MT Cell Viability Assay. O-GlcNAc-transferase (OGT), a known protein in ccRCC proliferation, was identified by bioinformatics analysis as a target of both miRNA and validated via luciferase reporter assay to confirm binding of each miR to the 3′ untranslated region (UTR). OGT protein expression was evaluated via western blotting. RESULTS: Luciferase assay confirmed specificity of miR-15a-5p and -26a-5p for the OGT UTR. Western blot analysis for OGT showed reduced expression following co-transfection of both miRNAs compared to negative control or individual transfection. Co-transfection of these miRNAs greatly reduced proliferation when compared to negative control or the individual transfections. CONCLUSION: Our results indicate that the dysregulation of miR-15a-5p and -26a-5p contribute cooperatively to the proliferation of ccRCC through their regulation of OGT. These results give insight into the pathogenesis of aggressive early stage ccRCC and suggest potential therapeutic targets for future research.
Purpose of Review Residency training is a pivotal educational step on the road to becoming a urologist. It combines both clinical and surgical instruction with the goal of producing proficient and compassionate surgeons and clinicians. In this review, we employ a SWOT analysis (Strengths, Weaknesses, Opportunities, and Threats) to investigate the current state of urologic residency training. Recent Findings Urology remains an attractive and competitive residency with varied and complex surgical and medical training. Areas for improvement include standardization of evaluation and feedback, improving resident wellness, and expanding the use of surgical simulation. Workforce issues such as the predicted urologist supply deficit and poor readiness to enter the business of medicine can be addressed at the residency level. Failure to attract and retain underrepresented minorities, increasing burden of student debt, and resident burnout are serious threats to our field. Summary Using a SWOT analysis we identify key areas for expansion, underscore valuable strengths, and provide a working roadmap for improvement of these formative years.
Differential microRNA (miRNA) expression can portend clear cell renal cell carcinoma (ccRCC) progression. In a previous study, we identified a subset of dysregulated miRNA in small renal masses, pT1 ccRCC (≤5 cm) that are associated with an aggressive phenotype. The present study investigated miRNA expression in clinical stage I (cT1) tumors (≤5 cm), comparing pathologic stage I (pT1) tumors to those upstaged to pathologic stage 3 (pT3) after surgery following identification of renal vein invasion or invasion into adjacent fat tissue within Gerota’s fascia. Twenty cT1 tumors were examined in an miRNA screening, 10 pT1 and 10 pT3 tumors. The ccRCC cell lines 786-O and Caki-1 were used to assess the impact of let-7c-5p and its protein target insulin-like growth factor 1 receptor (IGF1R). Cells were transfected with pre-let-7c-5p and assessed through cell proliferation, migration, and invasion assays. IGF1R expression was evaluated through Simple Western, and interaction between let-7c-5p and IGF1R was confirmed via luciferase reporter assay. Screening identified 20 miRNA, including let-7c-5p, that were dysregulated between pT1 and pT3 upstaged tumors. This miRNA was also downregulated in our previous study of pT1 tumors that progressed to metastatic disease. Transfection of ccRCC cells with pre-let-7c-5p significantly inhibited proliferation, migration, invasion, and IGF1R expression. These findings suggest that miRNA dysregulation is involved in ccRCC progression, specifically through invasion, and that let-7c-5p downregulation contributes to the aggressiveness of small ccRCC tumors, in part, through its regulation of IGF1R.
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