Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice

Abstract

AimNeural network oscillation at gamma frequency band (γ oscillation, 30–80 Hz) is synchronized synaptic potentials important for higher brain processes and altered in normal aging. Recent studies indicate that activation of dopamine 4 receptor (DR4) enhanced hippocampal γ oscillation of young mice and fully recovered the impaired hippocampal synaptic plasticity of aged mice, we determined whether this receptor is involved in aging-related modulation of hippocampal γ oscillation.MethodsWe recorded γ oscillations in the hippocampal CA3 region from young and aged C57bl6 mice and investigated the effects of dopamine and the selective dopamine receptor (DR) agonists on γ oscillation.ResultsWe first found that γ oscillation power (γ power) was reduced in aged mice compared to young mice, which was restored by exogenous application of dopamine (DA). Second, the selective agonists for different D1- and D2-type dopamine receptors increased γ power in young mice but had little or small effect in aged mice. Third, the D4 receptor (D4R) agonist PD168077 caused a large increase of γ power in aged mice but a small increase in young mice, and its effect is blocked by the highly specific D4R antagonist L-745,870 or largely reduced by a NMDAR antagonist. Fourth, D3R agonist had no effect on γ power of either young or aged mice.ConclusionThis study reveals DR subtype-mediated hippocampal γ oscillations is aging-related and DR4 activation restores the impaired γ oscillations in aged brain, and suggests that D4R is the potential target for the improvement of cognitive deficits related to the aging and aging-related diseases.

Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal–Hippocampal Coupling

“…Dopaminergic neurons in the VTA were shown to synchronize with substantial fractions of these cells at both delta and theta frequencies and gamma rhythm in the VTA was also modulated by delta rhythm in VTA and PFC and by the phase-coupled theta in HPC [ 21 ]. D4R agonists in high doses elicit aberrant gamma oscillations [ 28 ] comparable with that reported after administration of ketamine or other NMDA-R agonists [ 29 ]. Interestingly, ketamine’s action on gamma oscillation is at least partially depended on D4R in the thalamus but not in the PFC [ 29 ].…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…Furthermore, as D4Rs localized on both pyramidal and GABAergic neurons in the cortex, hippocampus, thalamus, globus pallidus , and substantia nigra [ 60 ], it has been hypothesized that selective D4R antagonists could, directly and indirectly, modulate glutamatergic transmission [ 60 ]. D4R seems to also be involved in the restoration of γ-oscillation in the hippocampal slices of aged mice brains, probably with a therapeutic effect on cognitive impairment related to ageing [ 61 ]. This effect is reported in hippocampal parvalbumin-positive GABA interneurons and parvalbumin-positive basket cells, which are critical for γ-oscillations, by double in situ hybridization and immunofluorescence histochemistry, confirming the crucial role of D4R in cognitive deficits [ 62 ].…”

Dopamine D4 Receptor Down-Regulates Renal Sodium Chloride Cotransporter via Ubiquitination-Associated Lysosome Degradation

“…The sources of drugs were: D4R agonist PD168077 (Tocris Bioscience, 1065/10) and antagonist L-745,870 (Tocris Bioscience, 1002/10) (43,44); NCC inhibitor metolazone (Met) (MedChemExpress, HY-B0209); Hydrochlorothiazide (HCTZ) (Sigma, H2910); Cycloheximide (CHX) (MedChemExpress, HY-12320); Chloroquine (CQ) (MedChemExpress, HY-17589A). The rabbit polyclonal D4R and chicken polyclonal NCC antibodies were generated and affinity-purified in our laboratory.…”