ABSTRACT
Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer's disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement. At the age of 7.5 and 10 months, transgenic mice also showed signs of nonspecific excitement and anxiety, depression-like state, and symptoms of cholinergic deficit. Our results suggest that appropriate age for behavioral tests in studies of effects of potential anti-Alzheimer drugs in transgenic V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) mice is 7.5-10 months.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/genetics , Animals , Anxiety/drug therapy , Anxiety/pathology , Anxiety/physiopathology , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Disease Models, Animal , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/pathology , Memory Disorders/physiopathology , Mice , Mice, Transgenic , Neuroprotective Agents/therapeutic useABSTRACT
Experiments on frog neuromuscular synapses using extracellular microelectrode recording of endplate currents (EPC) and nerve ending (NE) responses were performed to study the mechanisms of facilitation of quantum secretion of acetylcholine on replacement of extracellular Ca ions with Sr ions. Solutions with a Ca ion concentration of 0.5 mM (calcium solutions) or a Sr ion concentration of 1 mM (strontium solutions) were used; the basal levels of neurotransmitter secretion (in conditions of low-frequency stimulation) were essentially identical. In calcium solutions, the drop in EPC facilitation on paired-pulse stimulation as the interimpulse interval was increased from 5 to 500 msec was described by the sum of three exponential components - the early, the first, and the second. In strontium solutions, facilitation was decreased as compared with the level in calcium solutions predominantly because of decreases in the early and first components. At the same time, EPC facilitation in conditions of rhythmic stimulation (10 or 50 impulses/sec) in strontium solution was significantly increased as compared with the level in calcium solutions. In strontium solutions in conditions of high-frequency stimulation at 50 impulses/sec, there was also a marked decrease in the amplitude of the third phase of the NE response, reflecting NE potassium currents. These data lead to the conclusion that the facilitation sites underlying the first and early components had lower affinities for Sr ions than for Ca ions. Increases in facilitation in strontium solutions in conditions of high-frequency rhythmic activity resulted from two mechanisms: more marked widening of the NE action potential and an increase in the divalent cation influx current due to weak activation of the Ca2+-dependent potassium current in the presence of Sr ions, as well as the slow dynamics of the removal of Sr ions from the NE axoplasm as compared with that in the presence of Ca ions.
Subject(s)
Motor Endplate/physiology , Nerve Endings/physiology , Neurotransmitter Agents/metabolism , Strontium/metabolism , Acetylcholine/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Animals , Calcium/metabolism , Calcium/pharmacology , Culture Media/chemistry , Electric Stimulation , Motor Endplate/metabolism , Nerve Endings/metabolism , Potassium Channels/metabolism , Rana ridibunda , Solutions , Strontium/pharmacology , Tissue Culture Techniques/methodsABSTRACT
Rhythmic stimulation of nerve-muscle preparation of frog sternal muscle bathed in low-Ca(2+) saline increased the release of neurotransmitter (facilitation) and modified the shape of extracellular response of nerve terminal (decreased phase III amplitude). Iberiotoxin and 4-aminopyridine modified the dynamics these processes. We conclude that inactivation of potential-dependent K(+)-channels and activation of calcium-dependent K(+)-channels in frog motor nerve terminals during rhythmic activity modulate Ca(2+) influx into nerve terminals and contribute into facilitation of neurotransmitter secretion. The degree of these mechanisms depends on the rate of synaptic rhythmic activity.