Circuit formation in the adult brain

Neurons in the mammalian central nervous system display an enormous capacity for circuit formation during development but not later in life. In principle, new circuits could be also formed in adult brain, but the absence of the developmental milieu and the presence of growth inhibition and hundreds of working circuits are generally viewed as unsupportive for such a process. Here, we bring together evidence from different areas of neuroscience—such as neurological disorders, adult-brain neurogenesis, innate behaviours, cell grafting, and in vivo cell reprogramming—which demonstrates robust circuit formation in adult brain. In some cases, adult-brain rewiring is ongoing and required for certain types of behaviour and memory, while other cases show significant promise for brain repair in disease models. Together, these examples highlight that the adult brain has higher capacity for structural plasticity than previously recognized. Understanding the underlying mechanisms behind this retained plasticity has the potential to advance basic knowledge regarding the molecular organization of synaptic circuits and could herald a new era of neural circuit engineering for therapeutic repair

Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2.

Parvalbumin-expressing, fast-spiking basket cells are important for the generation of synchronous, rhythmic population activities in the hippocampus. We found that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells were selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC-2. Our data reveal a previously unknown cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons

Hierarchically Organized Minority Games

In this paper a hierarchical extension of the Minority Game is defined and studied. Numerical simulations show a special type of emergent global behavior between separated parts of the hierarchical structure, connected only through a normalized mean field quantity.Comment: 8 page

Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus

The diversity reflected by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information. Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. In this study, we used single-cell RNA-seq in morphologically identified parvalbumin interneurons (PV-INs), and studied their transcriptomic states in the morphological, physiological, and developmental domains. Overall, we find high transcriptomic similarity among PV-INs, with few genes showing divergent expression between morphologically different types. Furthermore, PV-INs show a uniform synaptic cell adhesion molecule (CAM) profile, suggesting that CAM expression in mature PV cells does not reflect wiring specificity after development. Together, our results suggest that while PV-INs differ in anatomy and in vivo activity, their continuous transcriptomic and homogenous biophysical landscapes are not predictive of these distinct identities

Deep Survey of GABAergic Interneurons: Emerging Insights From Gene-Isoform Transcriptomics

GABAergic interneuron diversity is a key feature in the brain that helps to create different brain activity patterns and behavioral states. Cell type classification schemes—based on anatomical, physiological and molecular features—have provided us with a detailed understanding of the distinct types that constitute this diversity and their contribution to brain function. Over recent years, the utility of single-cell RNAseq has majorly complemented this existing framework, vastly expanding our knowledge base, particularly regarding molecular features. Single-cell gene-expression profiles of tens of thousands of GABAergic cells from many different types are now available. The analysis of these data has shed new lights onto previous classification principles and illuminates a path towards a deeper understanding of molecular hallmarks behind interneuron diversity. A large part of such molecular features is synapse-related. These include ion channels and receptors, as well as key synaptic organizers and trans-synaptic signaling molecules. Increasing evidence suggests that transcriptional and post-transcriptional modifications further diversify these molecules and generate cell type-specific features. Thus, unraveling the cell type-specific nature of gene-isoform expression will be a key in cell type classification. This review article discusses progress in the transcriptomic survey of interneurons and insights that have begun to manifest from isoform-level analyses

Upregulated H-Current in Hyperexcitable CA1 Dendrites after Febrile Seizures

Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current (Ih) after experimental febrile seizures. Here, we examined febrile seizure-induced long-term changes in Ih and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic Ih was significantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced Ih is typically thought to be associated with decreased dendritic excitability, whole-cell dendritic recordings revealed a robust increase in action potential firing after febrile seizures. We turned to computational simulations to understand how the experimentally observed changes in Ih influence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in Ih resulted in a general enhancement of dendritic excitability, primarily due to the increased Ih-induced depolarization of the resting membrane potential overcoming the excitability-depressing effects of decreased dendritic input resistance. Taken together, these experimental and modeling results reveal that, contrary to the exclusively anti-convulsive role often attributed to increased Ih in epilepsy, the enhanced Ih can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus

Single-Cell RNA-Seq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles

Neurexins are key synaptic organizers that are expressed in thousands of alternatively spliced isoforms. Because transsynaptic neurexin interactions with different postsynaptic molecules are largely isoform dependent, a cell type-level census of different neurexin isoforms could predict molecular interactions relating to synapse identity and function. Using single-cell transcriptomics to study the origin of neurexin diversity in multiple murine mature and embryonic cell types, we have discovered shared neurexin expression patterns in developmentally related cells. By comparing neurexin profiles in immature embryonic neurons, we show that neurexin profiles are specified during early development and remain unchanged throughout neuronal maturation. Thus, our findings reveal ontogenetic stability and provide a cell type-level census of neurexin isoform expression in the cortex

Pcdh11x controls target specification of mossy fiber sprouting

Circuit formation is a defining characteristic of the developing brain. However, multiple lines of evidence suggest that circuit formation can also take place in adults, the mechanisms of which remain poorly understood. Here, we investigated the epilepsy-associated mossy fiber (MF) sprouting in the adult hippocampus and asked which cell surface molecules define its target specificity. Using single-cell RNAseq data, we found lack and expression of Pcdh11x in non-sprouting and sprouting neurons respectively. Subsequently, we used CRISPR/Cas9 genome editing to disrupt the Pcdh11x gene and characterized its consequences on sprouting. Although MF sprouting still developed, its target specificity was altered. New synapses were frequently formed on granule cell somata in addition to dendrites. Our findings shed light onto a key molecular determinant of target specificity in MF sprouting and contribute to understanding the molecular mechanism of adult brain rewiring

Transcriptomically-guided pharmacological experiments in neocortical and hippocampal NPY positive GABAergic interneurons

Cortical GABAergic interneurons have been shown to fulfil important roles by inhibiting excitatory principal neurons. Recent transcriptomic studies have confirmed seminal discoveries that used anatomic and electrophysiological methods highlighting the existence of multiple different classes of GABAergic interneurons. Although some of these studies have emphasized that inter-regional differences may exist for a given class, the extent of such differences remains unknown. To address this problem, we used single-cell Patch-RNAseq to characterize neuropeptide Y (NPY)-positive GABAergic interneurons in superficial layers of the primary auditory cortex (AC) and in distal layers of area CA3 in mice. We found that more than 300 genes are differentially expressed in NPY-positive neurons between these two brain regions. For example, the AMPA receptor (AMPAR) auxiliary subunit Shisa9/CKAMP44 and the 5HT2a receptor (5HT2aR) are significantly higher expressed in auditory NPY-positive neurons. These findings guided us to perform pharmacological experiments that revealed a role for 5HT2aRs in auditory NPY-positive neurons. Specifically, although the application of 5HT led to a depolarization of both auditory and CA3 NPY-positive neurons, the 5HT2aR antagonist ketanserin only reversed membrane potential changes in auditory NPY-positive neurons. Our study demonstrates the potential of single-cell transcriptomic studies in guiding directed pharmacological experiments

Commissural dentate granule cell projections and their rapid formation in the adult brain

Dentate granule cells (GCs) have been characterized as unilaterally projecting neurons within each hippocampus. Here, we describe a unique class, the commissural GCs, which atypically project to the contralateral hippocampus in mice. Although commissural GCs are rare in the healthy brain, their number and contralateral axon density rapidly increase in a rodent model of temporal lobe epilepsies. In this model, commissural GC axon growth appears together with the well-studied hippocampal mossy fiber sprouting and may be important for the pathomechanisms of epilepsy. Our results augment the current view on hippocampal GC diversity and demonstrate powerful activation of a commissural wiring program in the adult brain