Cortical wiring by synapse type-specific control of local protein synthesis.

Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. We identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of messenger RNA {mRNA} translation in a cell type-specific and synapse type-specific manner.

Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders.

Recent advances in genomics have revealed a wide spectrum of genetic variants associated with neurodevelopmental disorders at an unprecedented scale. An increasing number of studies have consistently identified mutations-both inherited and de novo-impacting the function of specific brain circuits. This suggests that, during brain development, alterations in distinct neural circuits, cell types, or broad regulatory pathways ultimately shaping synapses might be a dysfunctional process underlying these disorders.

Dissecting cellular diversity of cortical GABAergic cells across multiple modalities: A turning point in neuronal taxonomy.

Decoding the complexity of the brain requires an understanding of the architecture, function, and development of its neuronal circuits. Neuronal classifications that group neurons based on specific features/behaviors have become essential to further analyze the different subtypes in a systematic and reproducible way. A comprehensive taxonomic framework, accounting for multiple defining and quantitative features, will provide the reference to infer generalized rules for cells ascribed to the same neuronal type, and eventually predict cellular behaviors, even in the absence of experimental measures.

Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits.

The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here, we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex, respectively.

Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits.

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear.

The Microtubule Regulator NEK7 Coordinates the Wiring of Cortical Parvalbumin Interneurons.

Functional networks in the mammalian cerebral cortex rely on the interaction between glutamatergic pyramidal cells and GABAergic interneurons. Both neuronal populations exhibit an extraordinary divergence in morphology and targeting areas, which ultimately dictate their precise function in cortical circuits. How these prominent morphological differences arise during development is not well understood.

Molecular diversity underlying cortical excitatory and inhibitory synapse development.

The complexity and precision of cortical circuitries is achieved during development due to the exquisite diversity of synapse types that is generated in a highly regulated manner. Here, we review the recent increase in our understanding of how synapse type-specific molecules differentially regulate the development of excitatory and inhibitory synapses. Moreover, several synapse subtype-specific molecules have been shown to control the targeting, formation or maturation of particular subtypes of excitatory synapses.

Neural circuit dysfunction in mouse models of neurodevelopmental disorders.

Neuropsychiatric disorders arise from the alteration of normal brain developmental trajectories disrupting the function of specific neuronal circuits. Recent advances in human genetics have greatly accelerated the identification of genes whose variation increases the susceptibility for neurodevelopmental disorders, most notably for autism spectrum disorder (ASD) and schizophrenia. In parallel, experimental studies in animal models-most typically in mice-are beginning to shed light on the role of these genes in the development and function of specific brain circuits.

Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican.

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive.

Abnormal wiring of CCK basket cells disrupts spatial information coding.

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3).

Shaping Early Networks to Rule Mature Circuits: Little MiRs Go a Long Way.

Normative cortical processing depends on precise interactions between excitatory and inhibitory neurons. In this issue of Neuron, Lippi et al. (2016) identify miR-101 as a master regulator coordinating molecular programs during development that ultimately impact the activity of mature networks.

Focal adhesion kinase function in neuronal development.

During the development and maturation of the adult nervous system, several consecutive events, from neural induction to axon-dendrite arborization and synapse formation, contribute to the final exquisite specificity of neuronal networks. To accomplish this precise and healthy brain architecture, a coordinated rearrangement of the cytoskeleton in response to extracellular cues is essential. In this review, we propose focal adhesion kinase (FAK) as a key intracellular component for this command, and summarize different studies that support this hypothesis.

Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects.

Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth.

The establishment of neural circuits depends on the ability of axonal growth cones to sense their surrounding environment en route to their target. To achieve this, a coordinated rearrangement of cytoskeleton in response to extracellular cues is essential. Although previous studies have identified different chemotropic and adhesion molecules that influence axonal development, the molecular mechanism by which these signals control the cytoskeleton remains poorly understood.

Focal adhesion kinase modulates radial glia-dependent neuronal migration through connexin-26.

Focal adhesion kinase (FAK) is an intracellular kinase and scaffold protein that regulates migration in many different cellular contexts but whose function in neuronal migration remains controversial. Here, we have analyzed the function of FAK in two populations of neurons with very distinct migratory behaviors: cortical interneurons, which migrate tangentially and independently of radial glia; and pyramidal cells, which undergo glial-dependent migration. We found that FAK is dispensable for glial-independent migration but is cell-autonomously required for the normal interaction of pyramidal cells with radial glial fibers.

Neuregulin signaling, cortical circuitry development and schizophrenia.

Neuregulin-1 (Nrg1) and its receptor ErbB4 are encoded by genes that have been repeatedly linked to schizophrenia. Both genes are thought to play important roles in the development of brain circuitry, but their precise contribution to the disease process remains unknown. In this review, we summarize novel findings on the biological function of Nrg1 and ErbB4 in mice, with a focus on the development of inhibitory circuits in the cerebral cortex.

Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters.

Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet.

CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons.

In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown.

Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling.

Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown.

Focal adhesion kinase functions downstream of Sema3A signaling during axonal remodeling.

Axon refinement is a necessary event for sculpting the final wiring of neural circuits. Although some factors have been identified that cause axonal arbor remodeling, the molecular pathways transducing these extracellular signals to adhesion disassembly and the cytoskeleton are poorly understood. Here we show that conditional ablation of Focal adhesion kinase (Fak) abolishes axon remodeling induced by Semaphorin-3A (Sema3A) in hippocampal neurons.

Distribution of the dopamine innervation in the macaque and human thalamus.

We recently defined the thalamic dopaminergic system in primates; it arises from numerous dopaminergic cell groups and selectively targets numerous thalamic nuclei. Given the central position of the thalamus in subcortical and cortical interplay, and the functional relevance of dopamine neuromodulation in the brain, detailing dopamine distribution in the thalamus should supply important information. To this end we performed immunohistochemistry for dopamine and the dopamine transporter in the thalamus of macaque monkeys and humans to generate maps, in the stereotaxic coronal plane, of the distribution of dopaminergic axons.

BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin-beta-catenin interactions.

Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles "splitting" away from synaptic sites.

Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development.

Integrin-linked kinase (ILK) is a serine/threonine protein kinase that plays an important role in integrin signaling and cell proliferation. We used Cre recombinase (Cre)-loxP technology to study CNS restricted knock-out of the ilk gene by either Nestin-driven or gfap-driven Cre-mediated recombination. Developmental changes in ilk-excised brain regions are similar to those observed in mice lacking the integrin beta1 subunit in the CNS, including defective laminin deposition, abnormal glial morphology, and alterations in granule cell migration.