Dopamine D-4 receptor-deficient mice display cortical hyperexcitability

The dopamine D-4 receptor (D4R) is predominantly expressed in the frontal c ortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. How ever, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D4R agonists a nd antagonists the selectivity and efficacy of which have been rigorously d emonstrated in vivo. We have attempted to overcome this limitation by takin g a multidimensional approach to the characterization of mice completely de ficient in this receptor subtype. Electrophysiological current and voltage- clamp recordings were performed in cortical pyramidal neurons from wild-typ e and D4R-deficient mice. The frequency of spontaneous synaptic activity an d the frequency and duration of paroxysmal discharges induced by epileptoge nic agents were increased in mutant mice. Enhanced synaptic activity was al so observed in brain slices of wild-type mice incubated in the presence of the selective D4R antagonist PNU-101387G. Consistent with greater electroph ysiological activity, nerve terminal glutamate density associated with asym metrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D4R can f unction as an inhibitory modulator of glutamate activity in the FC.