Inhibitory neurons make up about a third of the neurons in the cerebral cortex, but researchers know little about how they take their place in the developing brain. New findings suggest that their migration is controlled by a back and forth interplay between a pair of dopamine receptors, modulated by several other molecules, researchers said today (November 18) at the annual meeting of the Society for Neuroscience.

Neurons that respond to GABA, the main inhibitory neurotransmitter in the brain, regulate cell proliferation and the formation of proper neural circuitry. Several developmental disorders including epilepsy and autism involve malfunctioning GABA neurons.

Last year, Harvard Medical School researcher Pradeep Bhide and colleagues showed in brain slices of mouse brains and in knockout mouse that activating the dopamine-1(D-1) receptor led to increased migration of GABA neurons, while activating the dopamine-2 (D-2) receptor decreased the movement of GABA neurons. "It is interesting that even in the embryonic brain, D-1 and D-2 produce opposite effects," Bhide said in his talk today.

More recently, Bhide's team exposed fetal mice to cocaine --which is known to disrupt dopamine transport -- and found that the homeobox transcription factor gene NKX2-1 also inhibits GABA migration. Whether NXK2-1 and the D-2 receptor interact directly is still unknown, although Bhide hypothesizes that cocaine, which upregulates the expression of NXK2-1, may be acting to alter dopamine levels, which in turn boosts D-2 receptor function

Bhide's team has also begun to look at other molecular players, such as the protein TorsinA, which is underexpressed in the developmental disorder Tortia Dystonia. Tortia Dystonia, a movement disorder that leads to the loss of motor control, also happens to be associated with a dopamine imbalance during early development.

In culture slice and knock-out experiments, Bhide's team showed that the loss of TorsinA decreases overall neuronal migration. His studies didn't identify a mechanism, but research in fibroblasts has shown that a drop in TorsinA boosts D-2 receptor and NKX21 activity -- both of which decrease GABA migration.

Bhide believes that TorsinA, like cocaine, somehow acts on the D-2 receptor by altering dopamine levels. The details remain to be worked out, but what?s certain is that an imbalance of dopamine levels in the brain can drastically alter development, he said.