In the cerebral cortex, GABAergic interneurons have evolved as a highly heterogeneous collection of cell types that are characterized by their unique spatial and temporal capabilities to influence neuronal circuits. Current estimates suggest that up to 50 different types of GABAergic neurons may populate the cerebral cortex, all derived from progenitor cells in the subpallium, the ventral aspect of the embryonic telencephalon. In this review, we provide an overview of the mechanisms underlying the generation of the distinct types of interneuron and their integration in cortical circuits. Interneuron diversity seems to emerge through the implementation of cell-intrinsic genetic programs in progenitor cells, which unfold over a protracted period of time until interneurons acquire mature characteristics. The developmental trajectory of interneurons is also modulated by activity-dependent, non-cell autonomous mechanisms that influence their ability to integrate in nascent circuits and sculpt their final distribution in the adult cerebral cortex.

GABAergic interneurons regulate neural circuit activity in the mammalian cerebral cortex. These cortical interneurons are structurally and functionally diverse. Here we use single-cell transcriptomics to study the origins of this diversity in mouse. We identify distinct types of progenitor cells and newborn neurons in the ganglionic eminences, the embryonic proliferative regions that give rise to cortical interneurons. These embryonic precursors show temporally and spatially restricted transcriptional patterns that lead to different classes of interneurons in the adult cerebral cortex. Our findings suggest that shortly after the interneurons become postmitotic, their diversity is already patent in their diverse transcriptional programs which subsequently guide further differentiation in the developing cortex.

The maintenance of appropriate arterial tone is critically important for normal physiological arterial function. However, the cellular and molecular mechanisms remain poorly defined. Here, we have shown that in the mouse aorta, resident macrophages prevented arterial stiffness and collagen deposition in the steady state. Using phenotyping, transcriptional profiling, and targeted deletion of Csf1r, we have demonstrated that these macrophages-which are a feature of blood vessels invested with smooth muscle cells (SMCs) in both mouse and human tissues-expressed the hyaluronan (HA) receptor LYVE-l. Furthermore, we have shown they possessed the unique ability to modulate collagen expression in SMCs by matrix metalloproteinase MMP-9-dependent proteolysis through engagement of LYVE-1 with the HA pericellular matrix of SMCs. Our study has unveiled a hitherto unknown homeostatic contribution of arterial LYVE-1 macrophages through the control of collagen production by SMCs and has identified a function of LYVE-1 in leukocytes.

The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum and regulate store-operated Ca2+ entry. STIM2 mediates cAMP/PKA-dependent phosphorylation of the AMPA receptor subunit GluA1 in excitatory neurons. In addition, STIM2 promotes cAMP-dependent surface delivery of GluA1.

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letion of the major adenylate kinase AK1 isoform, which catalyzes adenine nucleotide exchange, disrupts cellular energetic economy and compromises metabolic signal transduction. However, the consequences of deleting the AK1 gene on cardiac energetic dynamics and performance in the setting of ischemia-reperfusion have not been determined. Here, at the onset of ischemia, AK1 knockout mice hearts displayed accelerated loss of contractile force compared with wild-type controls, indicating reduced tolerance to ischemic stress. On reperfusion, AK1 knockout hearts demonstrated reduced nucleotide salvage, resulting in lower ATP, GTP, ADP, and GDP levels and an altered metabolic steady state associated with diminished ATP-to-P i and creatine phosphate-to-Pi ratios. Postischemic AK1 knockout hearts maintained ϳ40% of ␤-phosphoryl turnover, suggesting increased phosphotransfer flux through remaining adenylate kinase isoforms. This was associated with sustained creatine kinase flux and elevated cellular glucose-6-phosphate levels as the cellular energetic system adapted to deletion of AK1. Such metabolic rearrangements, along with sustained ATP-to-ADP ratio and total ATP turnover rate, maintained postischemic contractile recovery of AK1 knockout hearts at wild-type levels. Thus deletion of the AK1 gene reveals that adenylate kinase phosphotransfer supports myocardial function on initiation of ischemic stress and safeguards intracellular nucleotide pools in postischemic recovery. energy metabolism; adenine nucleotides; glycolysis; phosphotransfer; oxygen-18 phosphoryl labeling; phosphorus-31 nuclear magnetic resonance MAINTENANCE OF OPTIMAL CARDIAC function requires precise control of cellular nucleotide ratios and high-energy phosphoryl fluxes (11,22,30,32,33,36,40). Within the cellular energetic infrastructure, adenylate kinase has been recognized as an important phosphotransfer enzyme that catalyzes adenine nucleotide exchange (ATP ϩ AMP ª 2ADP) and facilitates transfer of both ␤-and ␥-phosphoryls in ATP (9,15,24,25,43). In this way, adenylate kinase doubles the energetic potential of ATP as a high-energy-phosphoryl carrying molecule and provides an additional energy source under conditions of increased demand and/or compromised metabolic state (13-15, 31, 35, 42). By regulating adenine nucleotide processing, adenylate kinase has been implicated in metabolic signal transduction (12,15,27). Indeed, phosphoryl flux through adenylate kinase has been shown to correlate with functional recovery in the metabolically compromised heart (30) and to facilitate intracellular energetic communication (3,9,13