Biology subjects

Randall, K. L.

Publications and source records attributed to Randall, K. L..

3 recordsLinked to original sources

bioRxiv2025

The retinal light response is modulated by an mGluR5-mediated retrograde signal from ON-bipolar cells to photoreceptors

The ON visual pathway is initiated by the deactivation of mGluR6, coupled to the opening of TRPM1 channels in retinal ON-bipolar cell dendrites. Here, we show that a second metabotropic glutamate receptor, mGluR5, is localized with TRPM1 and mGluR6 in the dendrites of ON-bipolar cells. To examine the function of mGluR5, we performed electroretinogram (ERG) recordings and found that the amplitude of the b-wave, which is primarily a measure of ON-bipolar cell light-driven activity, is reduced in mGluR5 knock-out mice compared to wild type. In the mGluR5-/- retina, we observed weaker mGluR6 immunofluorescence in the dendritic tips of ON-bipolar cells that could explain the smaller ERG b-wave. To observe the effect of mGluR5 without perturbing mGluR6 expression, wild type mice were injected with MTEP, an allosteric antagonist of mGluR5. MTEP increased the amplitude of the b-wave in response to dim stimuli and caused an inflection in the intensity-response plot for flashes in the mesopic range. In the brain, postsynaptic mGluR5 regulates presynaptic glutamate release via endocanabinoid-mediated retrograde signaling. Therefore, we tested the effect of the CB1 receptor antagonist, SR1417A, on the ERG and found that the b-wave was affected as by MTEP, including an inflection in the intensity-response. We further showed that the CB1 receptor agonist, ACEA, reversed the effects of MTEP. Together, our results indicate that mGluR5 plays a role in gain-control at the photoreceptor to ON-bipolar cell synapses, likely via an endocannabinoid-mediated retrograde feedback. Significance StatementLight-ON stimuli are transmitted from photoreceptors to ON-bipolar cells via three pathways, which are used under different light intensities, from dim to bright light. For each pathway, glutamate is the neurotransmitter released by rods and cones, and the postsynaptic role of the mGluR6-TRPM1 signaling cascade in ON-bipolar cells is well studied, with defects known to cause congenital stationary night blindness. We show here that mGluR5 is also present in ON-bipolar cell dendrites and regulates synaptic transmission between photoreceptors and ON-bipolar cells. In particular, we find that mGluR5 facilitates the transition between the different photoreceptor to ON-bipolar cell pathways via mGluR5-controlled retrograde release of endocannabinoids.

neuroscience↗

bioRxiv2023

DOCK2-deficiency causes defects in anti-viral T cell responses and poor control of herpes simplex virus infection

The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defence against infectious diseases. However, patients with these diseases are by definition rare. In addition, any analysis is complicated by treatments and co-morbid infections requiring the use of mouse models for detailed investigations. Here we develop a mouse model of DOCK2 immunodeficiency and demonstrate that these mice have delayed clearance of herpes simplex virus type 1 (HSV-1) infections. Further, we found that they have a critical, cell intrinsic role of DOCK2 in the clonal expansion of anti-viral CD8+ T cells despite normal early activation of these cells. Finally, while the major deficiency is in clonal expansion, the ability of primed and expanded DOCK2-deficient CD8+ T cells to protect against HSV-1-infection is also compromised. These results provide a contributing cause for the frequent and devastating viral infections seen in DOCK2-deficient patients and improve our understanding of anti-viral CD8+ T cell immunity.

immunology↗

bioRxiv2022

The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats

Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the haemodynamic and metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p=0.02) and rats (F(1,5)26.04, p=0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p=0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t=2.6(16) p=0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MBs hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MBs ability to enhance cerebral metabolism might be limited.

neuroscience↗