Activation of D1 receptor improved learning and memory and synaptic plasticity in Alzheimer’s model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder with complex etiology. Among the neurotransmitter abnormalities that have been investigated in AD, the dopaminergic system has been intensively studied as a key neurotransmitter system involved with emotion and cognition. The dopaminergic system undergoes several changes during the neuropathological aging process. In general, some studies suggested that dopamine plays a major role in synaptic plasticity mechanisms. Interestingly, in AD, the dysfunction of dopaminergic transmission has been hypothesized as a new player in the pathophysiology of AD. On the other hand, stimulation of dopaminergic input to the hippocampus, ventral tegmental area, improved working and spatial memory in mice model of Alzheimer’s disease. In this study we assessed the effect of dopamine receptors on learning and memory and synaptic plasticity in Alzheimer’s like disease mice model.MethodOne month after bilaterally intra hippocampal injection of cis‐ P tau, adult male mice received D1 and D2 receptor antagonist, after 5 minute, induced high‐frequency ventral tegmental area stimulation for 30 min/ 5 day, and animals were assessed for changes in learning and memory. Short term and long term memory was assessed respectively by Y maze and Barnes maze and also synaptic plasticity was studied by in vitro evoked‐ field potential recording.ResultHippocampal cis‐ P tau injection as a new mice model of Alzheimer’s disease produced spatial and working memory impairment and also disrupted long term potentiation in striatum radiatum of hippocampus. Applying VTA‐DBS ameliorated memory impairment, with no effects in the control group. Further, in vitro evoked field potential recording showed a restoration of long term potentiation (LTP).Using D2 receptor antagonist, has no effect on learning and memory improvement after stimulation of ventral tegmental area but using D1 receptor antagonist impaired learning and memory. Applying dopamine on hippocampal slice restored LTP and D1 receptor antagonist had no effect on LTP disruption, but D2 receptor antagonist restore LTP.ConclusionThese results indicate that ventral tegmental area stimulation might mitigate memory dysfunction and synaptic plasticity in cis‐P tau accumulation by D1 receptor and phasic release of dopamine.