Correction: Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP.

In the original version of this article, affiliation 3 was given as: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China". This has now been corrected to: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China".Additionally in the 'Data availability' section an incorrect accession code was given. The accession code has now been changed from 'PDB A9X (AnkG:GABARAPL)' to 'PDB 6A9X (AnkG:GABARAP)'.These errors have been corrected in both the PDF and HTML versions of the Article.

Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP.

GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

Patterns of nuclear and chloroplast genetic diversity and structure of manioc along major Brazilian Amazonian rivers.

Background and Aims: Amazonia is a major world centre of plant domestication, but little is known about how the crops were dispersed across the region. Manioc (Manihot esculenta) was domesticated in the south-western Amazon basin, and is the most important staple food crop that originated in Amazonia. Current contrasting distributions may reflect distinct histories of dispersal of bitter and sweet manioc landraces. To produce new insights into the evolutionary history of the crop, we investigated the contemporary genetic diversity and structure of bitter and sweet manioc along major Amazonian rivers. Methods: The patterns of genetic structure and diversity of wild and cultivated sweet and bitter manioc with four chloroplast and 14 nuclear microsatellite markers were evaluated. Results were interpreted in terms of the crop's dispersal. Key results: No phylogeographic patterns among rivers were detected, and genetic structure among rivers was confounded by the bitter-sweet divergence. However, differences in the distribution of nuclear diversity and somewhat distinctive patterns of genetic structure across rivers were observed within bitter and sweet manioc. Conclusions: Various pre-Columbian and post-European conquest events in the history of Amazonian occupation may explain the absence of clearer patterns of genetic structure. However, the wide distribution of the most common chloroplast haplotype agrees with an early dispersal of manioc across Brazilian Amazonia. Furthermore, differences in genetic structure and in the spatial distribution of genetic diversity suggest that bitter and sweet manioc had distinct dispersal histories. Knowledge about how prehistoric and contemporary Amazonian peoples manage their crops is valuable for the maintenance and conservation of the impressive diversity of their native crops.

Topography and architecture of visual and somatosensory areas of the agouti.

We analyzed the organization of the somatosensory and visual cortices of the agouti, a diurnal rodent with a relatively big brain, using a combination of multiunit microelectrode recordings and histological techniques including myelin and cytochrome oxidase staining. We found multiple representations of the sensory periphery in the parietal, temporal, and occipital lobes. While the agouti's primary (V1) and secondary visual areas seemed to lack any obvious modular arrangement, such as blobs or stripes, which are found in some primates and carnivores, the primary somatosensory area (S1) was internally subdivided in discrete regions, isomorphically associated with peripheral structures. Our results confirm and extend previous reports on this species, and provide additional data to understand how variations in lifestyle can influence brain organization in rodents.

S1 to S2 hind- and forelimb projections in the agouti somatosensory cortex: axon fragments morphological analysis.

The integration of cutaneous, proprioceptive, and motor information in area S2 seems to be essential for manual object recognition and motor control. Part of the inputs to S2 comes from area S1. However no detailed investigations of the morphology of this projection are available. In the present study we describe and quantify the morphology of axon fragments of S1 to S2 ipsilateral projections in the agouti somatosensory cortex. Two groups of projecting axon arbors in S2 were individually reconstructed in three dimensions using Neurolucida, after a single electrophysiological guided BDA injection in either the forelimb (n=4) or the hindlimb (n=4). Electrophysiological mapping was performed 15 days after injections, allowing the localization of S2. Cluster analysis of 40 fragments after hindlimb and 40 after forelimb distinguished two clusters of terminals designated as type I and type II. On average, Type I fragments had greater surface areas and segment lengths than type II fragments, whereas type II fragments had higher number of terminal boutons, number of segments and branching points/mm than type I fragments. Type I corresponded to 58% of the axons projecting from the hindlimb representation in S1 whereas 63% of the sample originating from the forelimb representation in S1 corresponded to type II axons. The results suggest possible parallel processing by two stereotyped classes of axon terminals in the S1 to S2 projections that may represent at least part of the circuitry groundwork associated with distinct somatomotor skills of these limbs in agoutis.

The organizational variability of the rodent somatosensory cortex.

Rodentia is the largest mammalian order, with more than 2,000 species displaying a great diversity of morphological characteristics and living in different ecological niches (terrestrial, semi-aquatic, arboreal and fossorial). Analysis of the organization of the somatosensory areas in six species of rodents allowed us to demonstrate that although these species share a similar neocortical blueprint with other eutherian mammals, important differences exist between homologous areas across different species, probably as a function of both lifestyle and peripheral sensory specializations typical of each species. We based this generalization on a phylogenetic comparison of the intrinsic organization of the primary somatosensory area (SI) across representatives of different rodent suborders. This analysis revealed considerable structural variability, including the differential expansion of cortical representation of specific body parts (cortical amplification) as well as the parcellation of areas into processing modules.

Callosal axon arbors in the limb representations of the somatosensory cortex (SI) in the agouti (Dasyprocta primnolopha).

The present report compares the morphology of callosal axon arbors projecting from and to the hind- or forelimb representations in the primary somatosensory cortex (SI) of the agouti (Dasyprocta primnolopha), a large, lisencephlic Brazilian rodent that uses forelimb coordination for feeding. Callosal axons were labeled after single pressure (n = 6) or iontophoretic injections (n = 2) of the neuronal tracer biotinylated dextran amine (BDA, 10 kD), either into the hind- (n = 4) or forelimb (n = 4) representations of SI, as identified by electrophysiological recording. Sixty-nine labeled axon fragments located across all layers of contralateral SI representations of the hindlimb (n = 35) and forelimb (n = 34) were analyzed. Quantitative morphometric features such as densities of branching points and boutons, segments length, branching angles, and terminal field areas were measured. Cluster analysis of these values revealed the existence of two types of axon terminals: Type I (46.4%), less branched and more widespread, and Type II (53.6%), more branched and compact. Both axon types were asymmetrically distributed; Type I axonal fragments being more frequent in hindlimb (71.9%) vs. forelimb (28.13%) representation, while most of Type II axonal arbors were found in the forelimb representation (67.56%). We concluded that the sets of callosal axon connecting fore- and hindlimb regions in SI are morphometrically distinct from each other. As callosal projections in somatosensory and motor cortices seem to be essential for bimanual interaction, we suggest that the morphological specialization of callosal axons in SI of the agouti may be correlated with this particular function.

Postnatal decrease of sodium current density in rat pituitary melanotropes following the onset of dopaminergic innervation.

Peptide secretion from rat melanotropes is tonically inhibited by a dopaminergic synaptic input that develops after birth and acts through D2 dopamine receptors. In this study, whole-cell Na(+) currents were recorded from melanotropes that were isolated from rat pituitary intermediate lobes at postnatal days 1-20 (P1-P20) and maintained in culture for 5-24 h. Coincident with the development of innervation, melanotropes exhibited a progressive decrease in peak Na(+) current density from P3 to P14. The decrease involved a 50% reduction in maximal Na(+) conductance with no detectable changes in channel gating. Subcutaneous injections of the D2 antagonist sulpiride, applied from P11 to P13, restored melanotrope Na(+) channel activity to pre-innervation levels. Thus, the activation of D2 receptors by the dopaminergic input reduces the functional expression of Na(+) channels in melanotropes.

L-type calcium channel activity regulates sodium channel levels in rat pituitary GH3 cells.

1. The effects of chronic pharmacological modulation of L-type Ca2+ channel activity on the cell surface expression of Na+ channels were examined in GH3 cells. 2. Prolonged inhibition (4-5 days) of L-channels with nimodipine caused a 50-60 % decrease in the peak amplitude of whole-cell Na+ currents recorded with the patch-clamp technique. On the contrary, prolonged exposure to the L-channel agonist Bay K 8644 induced an approximately 2.5-fold increase in peak Na+ current. In both cases, there were only minor changes in cell capacitance and no significant changes in Na+ channel gating properties. 3. Measurements of the specific binding of radiolabelled saxitoxin to intact cells showed that nimodipine treatment reduced the number of cell surface Na+ channels, whereas treatment with Bay K 8664 produced the opposite effect. The dual regulation of Na+ channel abundance explained the mentioned changes in Na+ current amplitude. 4. Plasma membrane Na+ channels had a half-life of approximately 17 h both in control cells and in cells treated with Bay K 8644, as estimated from the rate of decay of peak Na+ current after inhibition of protein synthesis with cycloheximide. Actinomycin D, an inhibitor of gene transcription, and also cycloheximide, occluded the stimulatory effect of Bay K 8644 on Na+ current density when measured over a 24 h period. 5. These findings indicate that the entry of Ca2+ through L-type channels influences in a positive way the number of functional Na+ channels in GH3 cells, and suggest that Ca2+ influx stimulates either Na+ channel gene expression or the expression of a regulatory protein that promotes translocation of pre-assembled Na+ channels into the plasma membrane.