UCSF

The transcriptional programs and signaling pathways involved in the generation of ventral midbrain dopaminergic (DA) neurons have been intensively researched but the process of DA neuron maturation and their integration into functional circuits is not well understood. These neural circuits involving DA neurons regulate reward and goal-directed behaviors and although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here we show that transforming growth factor β-1 (TGF-β1) uses an autocrine mechanism to promote the growth of DA axons and dendrites. Loss of TGF-β type II receptor (TβRII) in DA neurons causes a significant reduction in excitatory synaptic inputs, excitatory-inhibitory ratio and phasic firing. Interestingly, mouse mutants lacking TGF-β signaling in DA neurons exhibit hyperactivity and behavioral inflexibility in a reversal learning paradigm that tests their ability to relinquish learned behaviors and re-establish new stimulus-reward associations. Furthermore, preliminary data indicates that these conditional mutants are insensitive to the rewarding effects of morphine and fail to show morphine-induced conditioned place preference. These results reveal a previously unrecognized role of TGF-β signaling in regulating a delicate balance of excitatory and inhibitory synapse formation in local microcircuits involving DA and neighboring GABAergic neurons. They also underscore the potential contributions of TGF-β signaling to neuropsychiatric disorders such as addiction.