The mammalian telencephalon is considered the most complex of all biological structures. It comprises a large number of functionally and morphologically distinct types of neurons that coordinately control most aspects of cognition and behavior. The subpallium, for example, not only gives rise to multiple neuronal types that form the basal ganglia and parts of the amygdala and septum but also is the origin of an astonishing diversity of cortical interneurons. Despite our detailed knowledge on the molecular, morphological, and physiological properties of most of these neuronal populations, the mechanisms underlying their generation are still poorly understood. Here, we comprehensively analyzed the expression patterns of several transcription factors in the ventricular zone of the developing subpallium in the mouse to generate a detailed molecular map of the different progenitor domains present in this region. Our study demonstrates that the ventricular zone of the mouse subpallium contains at least 18 domains that are uniquely defined by the combinatorial expression of several transcription factors. Furthermore, the results of microtransplantation experiments in vivo corroborate that anatomically defined regions of the mouse subpallium, such as the medial ganglionic eminence, can be subdivided into functionally distinct domains.

Cortical pyramidal cells are generated from pallial neuroepithelial precursors, whereas GABAergic interneurons originate in subpallial germinal zones and migrate tangentially to reach the cortex. Using Cre-lox technology in transgenic mice and a series of molecular markers that subdivide the subpallial neuroepithelium into small domains, we fate-map precursor pools and identify interneurons generated from each domain. Cortical interneurons expressing calbindin, parvalbumin, and somatostatin are generated exclusively from Lhx6 (Lim homeobox 6)-expressing precursors in the medial ganglionic eminence (MGE). Martinotti cells that coexpress calretinin and somatostatin are generated from the dorsal region of the MGE neuroepithelium that expresses Nkx6.2 (NK2 transcription factor-related 6.2). Most neuropeptide Y-expressing cells and all bipolar calretinin-expressing interneurons are generated outside the MGE, from the germinal zones of the lateral/caudal ganglionic eminences that express Gsh2 (genomic screened homeobox 2). Our data demonstrate that subpallial neuroepithelial domains defined by expression of genetic determinants generate distinct interneuron subtypes, thereby contributing to the generation of cortical interneuron heterogeneity observed in the adult cortex.

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2loxP/loxP; Dat+/IRES-cre, referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.

GABA-containing (GABAergic) interneurons play an important role in the function of the cerebral cortex. Through mostly inhibitory mechanisms, interneurons control hyperexcitability and synchronize and shape the spatiotemporal dynamics of cortical activity underlying various brain functions. Studies over the past 10 years have demonstrated that, in most mammals, interneurons originate during development from the subcortical telencephalon-the subpallium-and reach the cerebral cortex through tangential migration. Until now, interneurons have been demonstrated to derive exclusively from two subpallial regions, the medial ganglionic eminence and the caudal ganglionic eminence. Here, we show that another subpallial structure, the preoptic area, is a novel source of cortical GABAergic interneurons in the mouse. In utero labeling and genetic lineage-tracing experiments demonstrate that neurons born in this region migrate to the neocortex and hippocampus, where they differentiate into a distinct population of GABAergic interneurons with relatively uniform neurochemical, morphological, and electrophysiological properties.