Abstract
Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease caused by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc)
We demonstrated that the administration of rolipram, a phosphodiesterase IV (PDE IV) inhibitor, restores the facilitation of memory extinction in PD model mice (PD mice) by stimulating the cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) pathway in the hippocampus [6]
5-HT4 receptor (5-HT4R) is highly expressed in the hippocampus, the stimulation of which leads to increased hippocampal pyramidal cell activity and serotonin release via activation of the cAMP/protein kinase A (PKA) pathway [13,14]
Summary
Parkinson’s disease (PD) is a neurodegenerative disease caused by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). Non-motor symptoms, including olfactory deficits, anxiety, and cognitive impairment, occur in patients with PD, sometimes appearing before the onset of motor dysfunction [2,3]. These non-motor symptoms, especially cognitive impairment, appear in about 40% of patients with PD [4]. We reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling in the hippocampus, which may cause cognitive impairment in PD [5,6]. The reason why hippocampal cAMP/CREB signaling is reduced in PD mice remains unclear
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