Biology subjects

Gardner, R. S.

Publications and source records attributed to Gardner, R. S..

3 recordsLinked to original sources

bioRxiv2024

Knock-in Kcnh2 Rabbit Model of Long QT Syndrome Type-2, Epilepsy, and Sudden Death

BackgroundLong QT Syndrome Type-2 (LQT2) is due to loss-of-function KCNH2 variants. KCNH2 encodes Kv11.1 that forms a delayed-rectifier potassium channel in the brain and heart. LQT2 is associated with arrhythmias, seizures, sudden cardiac death, and sudden unexpected death in epilepsy (SUDEP). The goal of the study is to develop a translational model that reproduces the neuro-cardiac electrical abnormalities and sudden death seen in people with LQT2. MethodsWe generated the first knock-in rabbit model of LQT2 (Kcnh2(+/7bp-del)), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit Kcnh2 gene. ResultsMutant Kcnh2 is expressed in the heart and brain and constitutes 11% of total Kcnh2 in Kcnh2(+/7bp-del) rabbits. Total Kcnh2, WT Kcnh2, and WT Kv11.1 expression is lower in Kcnh2(+/7bp-del) vs. WT rabbits. Kcnh2(+/7bp-del) rabbits exhibit prolonged cardiac ventricular repolarization (QTc, JTec, JTpc). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in Kcnh2(+/7bp-del) (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, p<0.003). 18.9% of Kcnh2(+/7bp-del) vs. 1.5% of WT rabbits died suddenly and spontaneously (p<0.003). We recorded 2 spontaneous lethal events in Kcnh2(+/7bp-del) rabbits: (1) sudden cardiac death and (2) seizure-mediated sudden death due to generalized tonic-clonic seizures, post-ictal generalized EEG suppression, bradycardia, ECG-T-wave inversion, focal cardiac activity, and asystole/death. ConclusionsWe developed the first genetic rabbit model of LQT2 that reproduces the cardiac and epileptic phenotypes seen in people with LQT2. Kcnh2(+/7bp-del) rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.

physiology↗

bioRxiv2024

Enhancement of response learning in male rats with intrastriatal infusions of a BDNF -TrkB agonist, 7,8-dihydroxyflavone

Enhancement of learning and memory by cognitive and physical exercise may be mediated by brain-derived neurotrophic factor (BDNF) acting at tropomyosin receptor kinase B (TrkB). Upregulation of BDNF and systemic administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), enhance learning of several hippocampus-sensitive tasks in rodents. Although BDNF and 7,8-DHF enhance functions of other brain areas too, these effects have mainly targeted non-cognitive functions. One goal of the present study was to determine whether 7,8-DHF would act beyond the hippocampus to enhance cognitive functions sensitive to manipulations of the striatum. Here, we examined the effects of intrastriatal infusions of 7,8-DHF on learning a striatum-sensitive response maze and on phosphorylation of TrkB receptors in 3-month-old male Sprague Dawley rats. Most prior studies of BDNF and 7,8-DHF effects on learning and memory have administered the drugs for days to months before assessing effects on cognition. A second goal of the present study was to determine whether a single drug treatment near the time of training would effectively enhance learning. Moreover, 7,8-DHF is often tested for its ability to reverse impairments in learning and memory rather than to enhance these functions in the absence of impairments. Thus, a third goal of this experiment was to evaluate the efficacy of 7,8-DHF in enhancing learning in unimpaired rats. In untrained rats, intrastriatal infusions of 7,8-DHF resulted in phosphorylation of TrkB receptors, suggesting that 7,8-DHF acted as a TrkB agonist and BDNF mimic. The findings that a single, intra-striatal infusion of 7,8-DHF 20 min before training enhanced response learning in rats suggest that, in addition to its trophic effects, BDNF modulates learning and memory through receptor mediated cell signaling events.

neuroscience↗

bioRxiv2021

Hippocampus-sensitive and striatum-sensitive learning one month after morphine or cocaine exposure in male rats

These experiments examined whether exposure to drugs of abuse altered the balance between hippocampal and striatal memory systems as measured long after drug treatments. Male rats received injections of morphine (5 mg/kg), cocaine (20 mg/kg), or saline for five consecutive days. One month later, rats were then trained to find food on a hippocampus-sensitive place task or a striatum-sensitive response task. Relative to saline controls, morphine-treated rats exhibited impaired place learning but enhanced response learning; prior cocaine exposure did not significantly alter learning on either task. Another set of rats was trained on a dual-solution T-maze that can be solved with either place or response strategies. While a majority (67%) of control rats used place solutions in this task, morphine treatment one month prior resulted in a shift to response solutions exclusively (100%). Prior cocaine treatment did not significantly alter strategy selection. Molecular markers related to learning and drug abuse were measured in the hippocampus and striatum one month after drug exposure in behaviorally untested rats. Protein levels of glial-fibrillary acidic protein (GFAP), an intermediate filament specific to astrocytes, increased significantly in the hippocampus after morphine, but not after cocaine exposure. Exposure to morphine or cocaine did not significantly change levels of brain-derived neurotrophic factor (BDNF) or a downstream target of BDNF signaling, glycogen synthase kinase 3{beta} (GSK3{beta}), in the hippocampus or striatum. Thus, exposure to morphine results in a long-lasting shift from hippocampal toward striatal dominance during learning. The effects of prior morphine injections on GFAP suggest that long-lasting alterations in hippocampal astrocytes may be associated with these behavioral strategy shifts.

neuroscience↗