Biology subjects

Quinn, C. J.

Publications and source records attributed to Quinn, C. J..

3 recordsLinked to original sources

bioRxiv2024

Impaired experience-dependent inter-areal network connectivity across the visual cortex in Fmr1 KO mice

Fragile X syndrome (FX) is the most prevalent inheritable form of autism spectrum disorder (ASD), characterized by hypersensitivity, difficulty in habituating to new sensory stimuli, and intellectual disability. Individuals with FX often experience visual perception and learning deficits. Visual experience leads to the emergence of the familiarity-evoked theta band oscillations in the primary visual cortex (V1) and the lateromedial area (LM) of mice. These theta oscillations in V1 and LM are synchronized with each other, providing a mechanism of sensory multi-areal binding. However, how this multi-areal binding and the corresponding theta oscillations are altered in FX is not known. Using iDISCO whole brain clearing with light-sheet microscopy, we quantified immediate early gene Fos expression in V1 and LM, identifying deficits in experience-dependent neural activity in FX mice. We performed simultaneous in vivo recordings with silicon probes in V1 and LM of awake mice and channelrhodopsin-2-assisted circuit mapping (CRACM) in acute brain slices to examine the neural activity and strength of long-range synaptic connections between V1 and LM in both wildtype (WT) and Fmr1 knockout (KO) mice, the model of FX, before and after visual experience. Our findings reveal synchronized familiarity-evoked theta oscillations in V1 and LM, the increased strength of V1[->]LM functional and synaptic connections, which correlated with the corresponding changes of presynaptic short-term plasticity in WT mice. The LM oscillations were attenuated in FX mice and correlated with impaired functional and synaptic connectivity and short-term plasticity in the feedforward (FF) V1[->]LM and feedback (FB) LM[->]V1 pathways. Finally, using 4Pi single-molecule localization microscopy (SMLM) in thick brain tissue, we identified experience-dependent changes in the density and shape of dendritic spines in layer 5 pyramidal cells of WT mice, which correlated with the functional synaptic measurements. Interestingly, there was an increased dendritic spine density and length in naive FX mice that failed to respond to experience. Our study provides the first comprehensive characterization of the role of visual experience in triggering inter-areal neural synchrony and shaping synaptic connectivity in WT and FX mice.

neuroscience↗

bioRxiv2023

Atrial t-tubules adopt a specialist developmental state while alterations to Ca2+ buffering maintain systolic Ca2+ during postnatal development

Transverse (t)-tubules ensure a uniform rise in calcium (Ca2+) and thus contraction in cardiac cells. Though more extensively studied in the ventricle, t-tubules also play a key role in the atria of large mammals, such as human, and their loss in heart failure is associated with impaired Ca2+ release and thus contractility. T-tubule restoration is therefore an ideal therapeutic target but the process of t-tubule formation is not understood. The aim of this study was to determine how t-tubules develop in the healthy atria and the impact this has on Ca2+ handling. Postnatal development was assessed in sheep from newborn through to adulthood. Atrial t-tubules were present at birth in the sheep atria and increased in density up until 3 months of age. In the latter part of development (3 months to adult) a lack of t-tubule growth but increase in cell width results in t-tubule density decreasing. In the newborn, despite reduced t-tubule density, we found the amplitude of the Ca2+ transient was maintained and this was associated with increases in the L-type Ca2+ current (ICa-L) and the Ca2+ content of the sarcoplasmic reticulum (SR). We suggest these changes are sufficient to overcome the elevated cytosolic Ca2+ buffering in the newborn and the decreased t-tubule density. We have shown the neonate atria is highly specialised to negate reduced central Ca2+ release through enhanced surface ICa-L and SR load. This maintains atrial function despite immature t-tubules highlighting important differences in Ca2+ handling in the newborn and heart failure atria where t-tubules are sparse.

physiology↗

bioRxiv2021

Disordered yet functional atrial t-tubules on recovery from heart failure

Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete loss of atrial t-tubules in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and if restored t-tubules are functional. Sheep were tachypaced to induce HF and recovered when pacing was stopped. Serial block face Scanning Electron Microscopy and confocal imaging were used to understand t-tubule ultrastructure and function. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and causality determined using expression studies. Sheep atrial t-tubules reappeared following recovery from HF. Despite being disordered (branched, longer and longitudinally arranged) recovered t-tubules triggered Ca2+ release and were associated with restoration of systolic Ca2+. Telethonin and myotubularin abundance correlated with t-tubule density and altered the density and structure of BIN1-driven tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. Recovery from HF restores atrial t-tubules and systolic Ca2+ and myotubularin facilitates this process. Atrial t-tubule restoration could present a new and viable therapeutic strategy. Brief SummaryThe loss of atrial transverse (t)-tubules and the associated dysfunction in heart failure is reversible and the protein myotubularin plays an important role.

physiology↗