Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link?

Experimental and clinical observations indicate that amyloid-β_1-42 (Aβ_1-42) peptide not only represents a major actor in neurodegenerative mechanisms but also induce hyperexcitation in individual neurons and neural circuits. In this abnormal excitability, possibly leading to seizures, the D1 dopamine (DA) receptors may play a role. Cerebrospinal fluid levels of Aβ_1-42 were measured in patients with late-onset epilepsy of unknown etiology. Moreover, the effect of amyloid peptide on the hippocampal epileptic threshold and synaptic plasticity and its link to D1 receptor function were tested in experimental mouse model of cerebral amyloidosis and in acute model of Aβ_1-42-induced neurotoxicity. Among 272 evaluated epileptic patients, aged >55 years, 35 suffered from late-onset epilepsy of unknown etiology. In these subjects, cerebrospinal fluid Aβ_1-42 levels were measured. The effects of Aβ_1-42, amyloid oligomers, and D1 receptor modulation on epileptic threshold were analyzed by electrophysiological recordings in the dentate gyrus of mice hippocampal slices. We found that Aβ_1-42 levels were significantly decreased in cerebrospinal fluid of patients with late-onset epilepsy of unknown etiology with respect to controls suggesting the cerebral deposition of this peptide in these patients. Aβ_1-42 enhanced epileptic activity in mice through a mechanism involving increased surface expression of D1 receptor, and this effect was mimicked by D1 receptor stimulation and blocked by SCH 23390, a D1 receptor antagonist. Aβ_1-42 may contribute to the pathophysiology of late-onset epilepsy of unknown origin. Our preclinical findings indicate that the D1 receptor is involved in mediating the epileptic effects of Aβ_1-42. This novel link between Aβ_1-42 and D1 receptor signaling might represent a potential therapeutic target.