Dopamine D4Receptor-Deficient Mice Display Cortical Hyperexcitability

• DOI: 10.1523/jneurosci.21-11-03756.2001
• Publication Date: 2018-04-05T01:30:23Z
• Authors: Marcelo Rubinstein; Carlos Cepeda; Raymond S. Hurst; Jorge Flores-Hern...; Marjorie A. Ariano; Tomás L. Falzone; Laura B. Kozell; Charles K. Meshul; James R. Bunzow; Malcolm J. Low; Michael S. Levine; David K. Grandy
• Keywords: Patch-Clamp Techniques; Dopamine; Presynaptic Terminals; Glutamic Acid; Convulsants; In Vitro Techniques; Bicuculline; Frontal cortex; Piperazines; Membrane Potentials; Attention deficit hyperactivity disorder; Mice; Mice, Neurologic Mutants; 03 medical and health sciences; 0302 clinical medicine; https://purl.org/becyt/ford/3.1; Animals; https://purl.org/becyt/ford/3; 4-Aminopyridine; Cerebral Cortex; Epilepsy; Dose-Response Relationship, Drug; Pyramidal Cells; Motor Cortex; Neural Inhibition; Immunohistochemistry; Dopamine D2 Receptor Antagonists; Glutamate; D4 receptor

The dopamine D4receptor (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 demonstratedin 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.