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.

The mechanisms controlling the assembly of brain nuclei are poorly understood. In the forebrain, it is typically assumed that the formation of nuclei follows a similar sequence of events that in the cortex. In this structure, projection neurons are generated sequentially from common progenitor cells and migrate radially to reach their final destination, whereas interneurons are generated remotely and arrive to the cortex through tangential migration. Using the globus pallidus as a model to study the formation of forebrain nuclei, we found that the development of this basal ganglia structure involves the generation of several distinct classes of projection neurons from relatively distant progenitor pools, which then assemble together through tangential migration. Our results thus suggest that tangential migration in the forebrain is not limited to interneurons, as previously thought, but also involves projection neurons and reveal that the assembly of forebrain nuclei is more complex than previously anticipated.

GABA-containing (GABAergic) interneurons comprise a very heterogeneous group of cells that are crucial for cortical function. Different classes of interneurons specialize in targeting specific subcellular domains of excitatory pyramidal cells or other interneurons, which provides cortical circuits with an enormous capability for information processing. As in other regions of the CNS, cortical interneuron diversity is thought to emerge from the genetic specification of different groups of progenitor cells within the subpallium. Most cortical interneurons originate from two main regions, the medial and the caudal ganglionic eminences (MGE and CGE, respectively). In addition, it has been shown that progenitors in the embryonic preoptic area (POA) also produce a small population of cortical GABAergic interneurons. Here, we show that the contribution of the POA to the complement of cortical GABAergic interneurons is larger than previously believed. Using genetic fate mapping and in utero transplantation experiments, we demonstrate that Dbx1-expressing progenitor cells in the POA give rise to a small but highly diverse cohort of cortical interneurons, with some neurochemical and electrophysiological characteristics that were previously attributed to MGE-or CGEderived interneurons. There are, however, some features that seem to distinguish POA-derived interneurons from MGE-or CGE-derived cells, such as their preferential laminar location. These results indicate that the mechanisms controlling the specification of different classes of cortical interneurons might be more complex than previously expected. Together with earlier findings, our results also suggest that the POA generates nearly 10% of the GABAergic interneurons in the cerebral cortex of the mouse.

Gamma-aminobutyric acid-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. Their influence on cortical function is remarkably diverse, a reflection of the large variety of interneuronal populations that exist in the mammalian cortex. Research over the past few years has rapidly transformed our understanding of their mechanisms underlying the generation of different classes of interneurons. In this review, we summarize recent progress on this process, progress which holds the promise of providing a rational framework for their classification, as well as means to understand their role in cortical processing.

The proopiomelanocortin gene ( POMC ) is expressed in a group of neurons present in the arcuate nucleus of the hypothalamus. Neuron-specific POMC expression in mammals is conveyed by two distal enhancers, named nPE1 and nPE2. Previous transgenic mouse studies showed that nPE1 and nPE2 independently drive reporter gene expression to POMC neurons. Here, we investigated the evolutionary mechanisms that shaped not one but two neuron-specific POMC enhancers and tested whether nPE1 and nPE2 drive identical or complementary spatiotemporal expression patterns. Sequence comparison among representative genomes of most vertebrate classes and mammalian orders showed that nPE1 is a placental novelty. Using in silico paleogenomics we found that nPE1 originated from the exaptation of a mammalian-apparent LTR retrotransposon sometime between the metatherian/eutherian split (147 Mya) and the placental mammal radiation (≈90 Mya). Thus, the evolutionary origin of nPE1 differs, in kind and time, from that previously demonstrated for nPE2, which was exapted from a CORE-short interspersed nucleotide element (SINE) retroposon before the origin of prototherians, 166 Mya. Transgenic mice expressing the fluorescent markers tomato and EGFP driven by nPE1 or nPE2, respectively, demonstrated coexpression of both reporter genes along the entire arcuate nucleus. The onset of reporter gene expression guided by nPE1 and nPE2 was also identical and coincidental with the onset of Pomc expression in the presumptive mouse diencephalon. Thus, the independent exaptation of two unrelated retroposons into functional analogs regulating neuronal POMC expression constitutes an authentic example of convergent molecular evolution of cell-specific enhancers.