Memantine-induced functional rewiring of the glutamate synapse in the striatum of dopamine transporter knockout rats

Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT^-/-) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.

The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT^-/- rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg^-1).

Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DAT^-/-rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT^-/- rats, thus restoring functional LTD.

A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.