Hippocampal inhibitory interneurones demonstrate pathway-and synapse-specific rules of transmission and plasticity, which are key determinants of their role in controlling pyramidal cell excitability. Mechanisms underlying long-term changes at interneurone excitatory synapses, despite their importance, remain largely unknown. We use two-photon calcium imaging and whole-cell recordings to determine the Ca 2+ signalling mechanisms linked specifically to group I metabotropic glutamate receptors (mGluR1α and mGluR5) and their role in hebbian long-term potentiation (

Background Prostate cancer (PC) is the most frequently diagnosed cancer in North American men. Pathologists are in critical need of accurate biomarkers to characterize PC, particularly to confirm the presence of intraductal carcinoma of the prostate (IDC-P), an aggressive histopathological variant for which therapeutic options are now available. Our aim was to identify IDC-P with Raman micro-spectroscopy (RμS) and machine learning technology following a protocol suitable for routine clinical histopathology laboratories. Methods and findings We used RμS to differentiate IDC-P from PC, as well as PC and IDC-P from benign tissue on formalin-fixed paraffin-embedded first-line radical prostatectomy specimens (embedded PLOS MEDICINE

Background Intraductal carcinoma of the prostate (IDC-P) is an independent biomarker of recurrence and survival with particular treatment response, yet no study has tested its response to radiotherapy. The aim of our project was to test the impact of adjuvant radiotherapy (ART) in patients with localized to locally advanced prostate cancer (PC) and IDC-P. Materials and methods We performed a retrospective study of men with pT2-T3 PC treated by radical prostatectomy (RP) with or without ART, from two centres (1993–2015). Exclusion criteria were the use of another type of treatment prior to biochemical recurrence (BCR), and detectable prostate- specific antigen (PSA) following RP or ART. Primary outcome was BCR (2 consecutive PSA ≥ 0.2 ng/ml). Patients were grouped by treatment (RP only /RP + ART), IDC-P status, and presence of high-risk features (HRF: Grade Groups 4–5, positive margins, pT3 stage). Results We reviewed 293 RP specimens (median follow-up 99 months, 69 BCR). Forty-eight patients (16.4%) were treated by RP + ART. Multivariate Cox regression for BCR indicated that IDC-P had the strongest impact (hazard ratio [HR] = 2.39, 95% confidence interval [CI]:1.44–3.97), while ART reduced the risk of BCR (HR = 0.38, 95%CI: 0.17–0.85). Other HRF were all significant except for pT3b stage. IDC-P[+] patients who did not receive ART had the worst BCR-free survival (log-rank P = 0.023). Furthermore, IDC-P had the same impact on BCR-free survival as ≥1 HRF (log-rank P = 0.955). Conclusion Men with IDC-P who did not receive ART had the highest BCR rates, and IDC-P had the same impact as ≥1 HRF, which are often used as ART indications. Once validated, ART should be considered in patients with IDC-P. Electronic supplementary material The online version of this article (10.1186/s13014-019-1267-3) contains supplementary material, which is available to authorized users.

Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer strongly associated with an increased risk of biochemical recurrence (BCR). However, approximately 40% of men with IDC-P remain BCR-free five years after radical prostatectomy. In this retrospective multicenter study, we aimed to identify histologic criteria associated with BCR for IDC-P lesions. A total of 108 first-line radical prostatectomy specimens were reviewed. In our test cohort (n = 39), presence of larger duct size (>573 µm in diameter), cells with irregular nuclear contours (CINC) (≥5 CINC in two distinct high-power fields), high mitotic score (>1.81 mitoses/mm2), blood vessels, and comedonecrosis were associated with early BCR (<18 months) (p < 0.05). In our validation cohort (n = 69), the presence of CINC or blood vessels was independently associated with an increased risk of BCR (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.09–4.96, p = 0.029). When combining the criteria, the presence of any CINC, blood vessels, high mitotic score, or comedonecrosis showed a stronger association with BCR (HR 2.74, 95% CI 1.21–6.19, p = 0.015). Our results suggest that IDC-P can be classified as low versus high-risk of BCR. The defined morphologic criteria can be easily assessed and should be integrated for clinical application following validation in larger cohorts.

Hippocampal GABAergic interneurons play key roles in regulating principal cell activity and plasticity. Interneurons located in stratum oriens/alveus (O/A INs) receive excitatory inputs from CA1 pyramidal cells and express a Hebbian form of long-term potentiation (LTP) at their excitatory input synapses. This LTP requires the activation of metabotropic glutamate receptors 1a (mGluR1a) and Ca 2+ entry via transient receptor potential (TRP) channels. However, the type of TRP channels involved in synaptic transmission at these synapses remains largely unknown. Using patch-clamp recordings, we show that slow excitatory postsynaptic currents (EPSCs) evoked in O/A INs are dependent on TRP channels but may be independent of phospholipase C. Using reverse transcription polymerase chain reaction (RT-PCR) we found that mRNA for TRPC 1, 3-7 was present in CA1 hippocampus. Using single-cell RT-PCR, we found expression of mRNA for TRPC 1, 4-7, but not TRPC3, in O/A INs. Using co-immunoprecipitation assays in HEK-293 cell expression system, we found that TRPC1 and TRPC4 interacted with mGluR1a. Coimmunoprecipitation in hippocampus showed that TRPC1 interacted with mGluR1a. Using immunofluorescence, we found that TRPC1 co-localized with mGluR1a in O/A IN dendrites, whereas TRPC4 localization appeared limited to O/A IN cell body. Down-regulation of TRPC1, but not TRPC4, expression in O/A INs using small interfering RNAs prevented slow EPSCs, suggesting that TRPC1 is an obligatory TRPC subunit for these EPSCs. Our findings uncover a functional role of TRPC1 in mGluR1a-mediated slow excitatory synaptic transmission onto O/A INs that could be involved in Hebbian LTP at these synapses.