Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia among elderly people. Amyloid beta (Ab) peptides in extracellular Ab plaques, produced from the amyloid precursor protein (APP) via sequential processing by b-and c-secretases, impair hippocampal synaptic plasticity, and cause cognitive dysfunction in AD patients. Here, we report that Ab peptides also impair another form of synaptic plasticity; cerebellar long-term depression (LTD). In the cerebellum of commonly used AD mouse model, APPswe/PS1dE9 mice, Ab plaques were detected from 8 months and profound accumulation of Ab plaques was observed at 18 months of age. Biochemical analysis revealed relatively high levels of APP protein and Ab in the cerebellum of APPswe/PS1dE9 mice. At pre-Ab accumulation stage, LTD induction, and motor coordination are disturbed. These results indicate that soluble Ab oligomers disturb LTD induction and cerebellar function in AD mouse model.

No abstract

Introduction: Sympathetic hyperactivity is strongly associated with ventricular arrhythmias and sudden cardiac death. Neuromodulation provides therapeutic options for ventricular arrhythmias by modulating cardiospinal reflexes and reducing sympathetic output at the level of the spinal cord. Dorsal root ganglion stimulation (DRGS) is a recent neuromodulatory approach; however, its role in reducing ventricular arrhythmias has not been evaluated. The aim of this study was to determine if DRGS can reduce cardiac sympathoexcitation and the indices for ventricular arrhythmogenicity induced by programmed ventricular extrastimulation. We evaluated the efficacy of thoracic DRGS at both low (20 Hz) and high (1 kHz) stimulation frequencies.Methods: Cardiac sympathoexcitation was induced in Yorkshire pigs (n = 8) with ventricular extrastimulation (S1/S2 pacing), before and after DRGS. A DRG-stimulating catheter was placed at the left T2 spinal level, and animals were randomized to receive low-frequency (20 Hz and 0.4 ms) or high-frequency (1 kHz and 0.03 ms) DRGS for 30 min. High-fidelity cardiac electrophysiological recordings were performed with an epicardial electrode array measuring the indices of ventricular arrhythmogenicity—activation recovery intervals (ARIs), electrical restitution curve (Smax), and Tpeak–Tend interval (Tp-Te interval).Results: Dorsal root ganglion stimulation, at both 20 Hz and 1 kHz, decreased S1/S2 pacing-induced ARI shortening (20 Hz DRGS −21±7 ms, Control −50±9 ms, P = 0.007; 1 kHz DRGS −13 ± 2 ms, Control −46 ± 8 ms, P = 0.001). DRGS also reduced arrhythmogenicity as measured by a decrease in Smax (20 Hz DRGS 0.5 ± 0.07, Control 0.7 ± 0.04, P = 0.006; 1 kHz DRGS 0.5 ± 0.04, Control 0.7 ± 0.03, P = 0.007), and a decrease in Tp-Te interval/QTc (20 Hz DRGS 2.7 ± 0.13, Control 3.3 ± 0.12, P = 0.001; 1 kHz DRGS 2.8 ± 0.08, Control; 3.1 ± 0.03, P = 0.007).Conclusions: In a porcine model, we show that thoracic DRGS decreased cardiac sympathoexcitation and indices associated with ventricular arrhythmogenicity during programmed ventricular extrastimulation. In addition, we demonstrate that both low-frequency and high-frequency DRGS can be effective neuromodulatory approaches for reducing cardiac excitability during sympathetic hyperactivity.

Background Neuraxial modulation, including spinal cord stimulation, reduces cardiac sympathoexcitation and ventricular arrhythmogenesis. There is an incomplete understanding of the molecular mechanisms through which spinal cord stimulation modulates cardiospinal neural pathways. We hypothesize that spinal cord stimulation reduces myocardial ischemia/reperfusion induced sympathetic excitation and ventricular arrhythmias through γ-aminobutyric acid (GABA) mediated pathways in the thoracic spinal cord. Methods Yorkshire pigs were randomized to Control (n=11), Ischemia/reperfusion (n=16), Ischemia/reperfusion+Spinal cord stimulation (n=17), Ischemia/reperfusion+Spinal cord stimulation +GABAA or GABAB receptor antagonist (GABAA, n=8, GABAB, n=8, and Ischemia/reperfusion+GABA transaminase inhibitor (GABAculine, n=8). A 4-pole spinal cord stimulation lead was placed epidurally (T1-T4) GABA modulating pharmacologic agents were administered intrathecally. Spinal cord stimulation at 50 Hertz was applied 30-min prior to ischemia. A 56-electrode epicardial mesh was used for high-resolution electrophysiological recordings, including activation recovery intervals and ventricular arrhythmia scores.. Immunohistochemistry and Western blots were performed to measure GABA receptor expression in the thoracic spinal cord. Results Cardiac ischemia led to myocardial sympathoexcitation with reduction in activation recovery interval (mean±SD: -42 ± 11%), which was attenuated by spinal cord stimulation (-21 ± 17%, P=0.001). GABAA and GABAB receptor antagonists abolished spinal cord stimulation attenuation of sympathoexcitation (GABAA -9.7 ± 9.7%, P=0.043 vs Ischemia/reperfusion + Spinal cord stimulation. GABAB -13 ± 14%, P=0.012 vs Ischemia/reperfusion + Spinal cord stimulation), while GABAculine alone caused a therapeutic effect similar to spinal cord stimulation (-4.1 ± 3.7%, P=0.038 vs Ischemia/Reperfusion). The ventricular arrhythmia score supported the above findings. Spinal cord stimulation during ischemia/reperfusion increased GABAA receptor expression with no change in GABAB receptor expression. Conclusions Thoracic spinal cord stimulation reduces ischemia/reperfusion-induced sympathoexcitation and ventricular arrhythmias through activation of GABA signaling pathways. These data support the hypothesis that spinal cord stimulation-induced release of GABA activates inhibitory interneurons to decrease primary afferent signaling from superficial dorsal horn to sympathetic output neurons in the intermediolateral nucleus.

No abstract