Altered synaptic currents,mitophagy,mitochondrial dynamics in Alzheimer's disease models and therapeutic potential of Dengzhan Shengmai capsules intervention

Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these pathological changes remain unclear.In this study,we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models.The investigations included behavioural tests,brain magnetic resonance imaging(MRI),liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis,Nissl staining,thioflavin-S staining,enzyme-linked immunosorbent assay,Golgi-Cox staining,transmission electron microscopy(TEM),immunofluorescence staining,proteomics,adenosine triphosphate(ATP)detection,mitochondrial membrane potential(MMP)and reactive oxygen species(ROS)assessment,mitochondrial morphology analysis,electrophysiological studies,Western blotting,and molecular docking.The results revealed changes in synaptic currents,mitophagy,and mitochondrial dynamics in the AD models.Remarkably,intervention with Dengzhan Shengmai(DZSM)capsules emerged as a pivotal element in this investigation.Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention,which notably amplified the frequency and amplitude of synaptic transmission.The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions,including the hippocampal CA3,primary cingular cortex,prelimbic system,and dysgranular insular cortex.DZSM intervention led to increased IDE levels,augmented long-term potential(LTP)amplitude,and enhanced dendritic spine density and length.Moreover,DZSM intervention led to favourable changes in mitochondrial parameters,including ROS expression,MMP and ATP contents,and mitochondrial morphology.In conclusion,our findings delved into the realm of altered synaptic currents,mitophagy,and mitochondrial dynamics in AD,concurrently highlighting the therapeutic potential of DZSM intervention.

Biphasic Cholinergic Modulation of Reverberatory Activity in Neuronal

Acetylcholine(ACh)is an important neuromod-ulator in various cognitive functions.However,it is unclear how ACh influences neural circuit dynamics by altering cellular properties.Here,we investigated how ACh influ-ences reverberatory activity in cultured neuronal networks.We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses,but to a much lesser extent at high doses.Moreover,high doses of ACh caused a longer duration of evoked reverberation,and a higher occur-rence of spontaneous activity.With whole-cell recording from single neurons,we found that ACh inhibited excita-tory postsynaptic currents(EPSCs)while elevating neu-ronal firing in a dose-dependent manner.Furthermore,all ACh-induced cellular and network changes were blocked by muscarinic,but not nicotinic receptor antagonists.With computational modeling,we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations.Thus,ACh modulates network dynamics in a biphasic fashion,probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.