Dopamine D4 receptor-deficient mice display cortical hyperexcitability.
The dopamine D(4) receptor (D(4)R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D(4)R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D(4)R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D(4)R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC.
Rubinstein
M
M
Instituto de Investigaciones en Ingenieria Genética y Biologia Molecular, Consejo Nacional de Investigaciones Cientificas y Técnicas and Departamento de Ciencias Biológicas, Universidad de Buenos Aires, Argentina. mrubins@dna.uba.ar
Cepeda
C
C
Hurst
R S
RS
Flores-Hernandez
J
J
Ariano
M A
MA
Falzone
T L
TL
Kozell
L B
LB
Meshul
C K
CK
Bunzow
J R
JR
Low
M J
MJ
Levine
M S
MS
Grandy
D K
DK
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003292:Convulsants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008818:Mice, Neurologic Mutants; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics; D050638:Receptors, Dopamine D4; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D015761:4-Aminopyridine; D001640:Bicuculline; D003292:Convulsants; D004298:Dopamine; D065127:Dopamine D2 Receptor Antagonists; D018698:Glutamic Acid; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D013449:Sulfonamides; C493600:Drd4 protein, mouse; C100448:sonepiprazole; D000096926:Benzenesulfonamides