The Effect And Synaptic Mechanisms Of Activation Of Dopamine Receptor On The Hippocampal Network Oscillations In Aged Mice

BackgroundHippocampal neuronal network y oscillation is closely related to learning and memory. Dopaminergic neurons of ventral tegmental area (VTA) project to hippocampal and regulate the function of hippocampal dependent learning and memory. A hall mark of aging and ageing related diseases such as Alzheimer’s (AD) diseases is the decline of learning and memory. Aging is also accompanied by the damage to dopaminergic neurons and y oscillations. It is not clear that the activation of Dopamine Receptor (DR) can affect the y oscillation of aged mice. This study will provide new insight into aging related decline of learning and memory and will have significance for the development of drugs for the prevention and treatment of aging-and AD-related decline of learning and memory.ObjectivesThe aims of this study are to investigate the effect of Dopamine and the different subtypes of DR agonists on y oscillations and the mechanisms, and whether these effects are aging-dependent.Methods1 Behavioral test-Morris water maze (MWM) MWM is used to test the age-related changes in the functions of learning, memory.2 Recording of neural network oscillationThe recording of brain slices were adapting a temperature controlled (30℃～32℃) interface-style bath perfusion system.The perfusion solution is ACSF (pH: 7.35～7.5, a flow rate of 2-3 ml/min), which is filled with a mixed gas (95% O2+5% CO2). C57BL6 mice of different ages were anesthesed with chloral hydrate, perfused with 0℃ cutting-ACSF through the left ventricle until the limbs turned white.Horizontal hippocampal slices were cut (350μm) using a VT1000S vibrating slicer. The mouse hippocampal slices were quickly transferred to the recording chamber, and the extracellular microelectrode recording was made one hour incubation.Kainate receptor agonist (Kainate) was used to induce y (20～60 Hz). The agonists or antagonists of DA were used to determine the role of DA in the neural network oscillation.3 Brain slice patch clampThe hippocampal slices were transferred to the submerged chamber.Single-cell patch-clamp recording was used to monitor neural firing or synaptic currents. The effects of DA and the different subtypes of DR agonists on the role of action potentials and synaptic currents were investigated.4 Statistical AnalysisStatistical results were express as mean ± standard error of the mean. The Sigmastat software was used for the statistical analysis. It is considered ststistically significant significance of the results, if P< 0.05.Results1. The MWM and the field potential recordings showed that learning and memory function and y oscillations in aged mice (18-20 months old) were damaged.2. In young mice (3-6 months old), dopamine had no significant effect on the y oscillations, D4R agonist increases the yoscillation and D1R agonist inhibits y oscillations in aged mice, D4R agonist suppressed y oscillation,dopamine also showed an inhibition on y oscillations, but the role of D1R agonist was decreasd.3. Patch clamp recordings from brain slices showed the sAHP amplitude was an age-dependently increased.4. The amplitude of mIPSC of hippocampal neurons was aging-related increased, but the frequency of mIPSC was aging-related decreased. D4R agonist significantly enhanced the amplitude of mlPSC in young mice, but significantly reduced the amplitude of mlPSC in aged mice; D4R agonists did not affect the frequency of mIPSC in young mice, but significantly decreased the frequency of mlPSC in aged mice.ConclusionsThe cognitive function of learning and memory and γ oscillation of aged mice was significantly impaired. Dopamine and specific dopamine receptor agonists have different effects on γ oscillations in different age groups. Dopamine inhibited the γ oscillations of aged mice, which may be related the reversal of DR4 effect’s on γ oscillations. The inhibition of DR4 on γ oscillations in aged mice may be related to the reduced mlPSC both in amplitude and frequency in aged mice. The inhibition of mlPSC may be linked to the increase of sAHP amplitude, which may cause the decline of neuronal excitability, leading to a reduction of inhibitory synaptic transmission, and the damage of γ oscillations.