Asynchronous Transmitter Release from Cholecystokinin-Containing Inhibitory Interneurons Is Widespread and Target-Cell Independent

Neurotransmitter release at most central synapses is synchronized to the timing of presynaptic action potentials. Here we show that 3 classes of DSI-expressing, CCK-containing, hippocampal interneurons show highly asynchronous release in response to trains of action potentials. This asynchrony is correlated to the class of presynaptic interneuron but is unrelated to their postsynaptic cell target. Asynchronous- and synchronous release from CCK-containing interneurons show a slightly different calcium dependence such that the proportion of asynchronous release increases with external calcium concentration possibly suggesting that the modes of release are mediated by different calcium sensors. Asynchronous IPSCs include very large (up to 500 pA/7nS) amplitude events, which persist in low extracellular calcium and strontium, showing that they result from quantal transmitter release at single release sites. Finally we show that asynchronous release is prominent in response to trains of presynaptic spikes which mimic natural activity of CCK-containing interneurons. That asynchronous release from CCK-containing interneurons is a widespread phenomenon indicates a fundamental role for these cells within the hippocampal network that is distinct from the phasic inhibition provided by PV-containing interneurons

Hippocampal GABAergic inhibitory interneurons

In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies

Teaching Science Students How to Think

Scientific thinking is more than just critical thinking. Teaching the full range of ways to think like a scientist who practices high quality science is rare. A new core subject in the Bachelor of Science at the University of Newcastle was developed to allow students to explore six different ways to thinking scientifically through understanding what high-quality science is and contrasting it with poor science and non-science (pseudoscience). Our evaluation indicates that learning about how to think scientifically and be a scientist who practices high quality science is a skill that is valued by and relevant to first year undergraduate students. An evidence-based pedagogy including active learning, participatory learning, student-centred learning, constructive alignment and quality formative and summative feedback to students can support high learning outcomes

Common Origins of Hippocampal Ivy and Nitric Oxide Synthase Expressing Neurogliaform Cells

GABAergic interneurons critically regulate cortical computation through exquisite spatio-temporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although nNOS+ interneurons constitute the largest hippocampal interneuron cohort their origin and specification remain unknown. Thus, as neurogliaform (NGC) and Ivy cells (IvC) represent the main nNOS+ interneurons we investigated their developmental origins. Although considered distinct interneuron subtypes NGCs and IvCs exhibited similar neurochemical and electrophysiological signatures including NPY expression and late-spiking. Moreover, lineage analyses, including loss-of-function experiments and inducible fate-mapping, indicated that nNOS+ IvCs and NGCs are both derived from medial ganglionic eminence (MGE) progenitors under control of the transcription factor Nkx2-1. Surprisingly, a subset of NGCs lacking nNOS arises from caudal ganglionic eminence (CGE) progenitors. Thus, while nNOS+ NGCs and IvCs arise from MGE progenitors, a CGE origin distinguishes a discrete population of nNOS-NGCs

A degree for today’s scientists: Demystifying the more-than-single disciplinary journey for students

Students commencing a science degree are most often interested in a particular discipline and see themselves graduating as a biologist, a chemist, a mathematician or physicist etc. (McInnis et al., 2000 & our own student surveys). In preparing for a major restructure of the Bachelor of Science at the University of Newcastle, we realized we needed to gently change the perceptions of commencing student about their potential graduate destinations. Our goal for students is to make explicit the full range of contemporary workforce relevant options, rather than emphasize only those that align with the existing ‘stereotypes’ about what scientists do. A more-than-disciplinary approach in teaching science knowledge and skills not only provides essential embedded transferable or entrepreneurial skills but also allows our graduates to open up broader career opportunities. The restructured Bachelor of Science degree was designed around an explicit more-than-disciplinary approach, with first-year having a multidisciplinary focus, the second year being an interdisciplinary year and third year students engaging in a transdisciplinary capstone experience. This presentation will discuss how the Bachelor of Science degree at the University of Newcastle will explicitly give our students the skills and knowledge to navigate the more-than-disciplinary journey in becoming a contemporary scientist

Molecular dissection of Neuroligin 2 and Slitrk3 reveals an essential framework for GABAergic synapse development

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development

Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

Background We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. Methods Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. Results RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%). The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. Conclusion The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastom