RT Journal Article SR Electronic T1 Dopamine D4 Receptor-Deficient Mice Display Cortical Hyperexcitability JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3756 OP 3763 DO 10.1523/JNEUROSCI.21-11-03756.2001 VO 21 IS 11 A1 Marcelo Rubinstein A1 Carlos Cepeda A1 Raymond S. Hurst A1 Jorge Flores-Hernandez A1 Marjorie A. Ariano A1 Tomás L. Falzone A1 Laura B. Kozell A1 Charles K. Meshul A1 James R. Bunzow A1 Malcolm J. Low A1 Michael S. Levine A1 David K. Grandy YR 2001 UL http://www.jneurosci.org/content/21/11/3756.abstract AB The dopamine D4 receptor (D4R) 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 D4R 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 D4R-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 D4R 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 D4R can function as an inhibitory modulator of glutamate activity in the FC.