Aberrant regulation of synchronous network activity by the attention-deficit/hyperactivity disorder-associated human dopamine D4 receptor variant D4.7 in the prefrontal cortex.

KEY POINTS: The hD4.7 variant has been linked to attention-deficit/hyperactivity disorder (ADHD); however, the underlying mechanism is unknown. We found that activation of hD4.7 induced over-suppression of glutamatergic excitatory network bursts and under-suppression of GABAergic inhibitory network bursts in the prefrontal cortex (PFC) circuitry. Methylphenidate, a psychostimulant drug used to treat ADHD, normalized the effects of hD4.7 on synchronous network bursts in PFC pyramidal neurons. The findings of the present study suggest that the aberrant regulation of PFC synchronous network activity by hD4.7 may underlie its involvement in ADHD. A unique feature of the human D4 receptor (hD4 R) gene is the existence of a large number of polymorphisms in exon 3 coding for the third intracellular loop, which consists of a variable number of tandem repeats. The hD4 R variants with long repeats have been linked to attention-deficit/hyperactivity disorder (ADHD); however, the underlying mechanism is unknown. Emerging evidence suggests that selective attention is controlled by the rhythmic synchronization in the prefrontal cortex (PFC) and its connected networks. In the present study, we examined the role of hD4 R variants in regulating PFC synchronous network activity. D4 R knockout mice with viral infection of hD4.4 or hD4.7 in the medial PFC were used. Whole-cell patch-clamp recordings were performed to examine the effects of activating hD4.x on the spontaneous large scale correlated activity in PFC pyramidal neurons. We found that, compared to the normal four-repeat variant hD4.4, the ADHD-linked variant hD4.7 induces more suppression of glutamatergic excitatory network bursts and less suppression of GABAergic inhibitory network bursts in the PFC circuitry. Methylphenidate, a psychostimulant drug used to treat ADHD, normalized the effects of hD4.7 on synchronous network bursts in PFC pyramidal neurons. These results reveal the differential effects of hD4 R variants on the integrated excitability of PFC circuits. It is suggested that the aberrant regulation of PFC network activity by hD4.7 may underlie its involvement in ADHD. The methylphenidate-induced normalization of synaptic circuitry regulation may contribute to its effectiveness in ADHD treatment.