It takes two to tango: Rycals and ATP snuggle up to bind ryanodine receptors.

In this issue of Structure, Melville and colleagues used cryo-EM to study the binding of ryanodine receptors to Rycals, compounds with the potential to treat skeletal and cardiac muscle disorders. Unexpectedly, they found that Rycal packs against an ATP in a peripheral pocket, which stabilizes the closed channel state.

The Scanpaths of Subjects with Developmental Prosopagnosia during a Face Memory Task.

The scanpaths of healthy subjects show biases towards the upper face, the eyes and the center of the face, which suggests that their fixations are guided by a feature hierarchy towards the regions most informative for face identification. However, subjects with developmental prosopagnosia have a lifelong impairment in face processing. Whether this is reflected in the loss of normal face-scanning strategies is not known. The goal of this study was to determine if subjects with developmental prosopagnosia showed anomalous scanning biases as they processed the identity of faces. We recorded the fixations of 10 subjects with developmental prosopagnosia as they performed a face memorization and recognition task, for comparison with 8 subjects with acquired prosopagnosia (four with anterior temporal lesions and four with occipitotemporal lesions) and 20 control subjects. The scanning of healthy subjects confirmed a bias to fixate the upper over the lower face, the eyes over the mouth, and the central over the peripheral face. Subjects with acquired prosopagnosia from occipitotemporal lesions had more dispersed fixations and a trend to fixate less informative facial regions. Subjects with developmental prosopagnosia did not differ from the controls. At a single-subject level, some developmental subjects performed abnormally, but none consistently across all metrics. Scanning distributions were not related to scores on perceptual or memory tests for faces. We conclude that despite lifelong difficulty with faces, subjects with developmental prosopagnosia still have an internal facial schema that guides their scanning behavior.

Calcium Channelopathies: Structural Insights into Disorders of the Muscle Excitation-Contraction Complex.

Ion channels are membrane proteins responsible for the passage of ions down their electrochemical gradients and across biological membranes. In this, they generate and shape action potentials and provide secondary messengers for various signaling pathways. They are often part of larger complexes containing auxiliary subunits and regulatory proteins. Channelopathies arise from mutations in the genes encoding ion channels or their associated proteins. Recent advances in cryo-electron microscopy have resulted in an explosion of ion channel structures in multiple states, generating a wealth of new information on channelopathies. Disease-associated mutations fall into different categories, interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating. Prime examples of these are Ca2+-selective channels expressed in myocytes, for which multiple structures in distinct conformational states have recently been uncovered. We discuss the latest insights into these calcium channelopathies from a structural viewpoint.

Perceptual Learning of Faces: A Rehabilitative Study of Acquired Prosopagnosia.

Despite many studies of acquired prosopagnosia, there have been only a few attempts at its rehabilitation, all in single cases, with a variety of mnemonic or perceptual approaches, and of variable efficacy. In a cohort with acquired prosopagnosia, we evaluated a perceptual learning program that incorporated variations in view and expression, which was aimed at training perceptual stages of face processing with an emphasis on ecological validity. Ten patients undertook an 11-week face training program and an 11-week control task. Training required shape discrimination between morphed facial images, whose similarity was manipulated by a staircase procedure to keep training near a perceptual threshold. Training progressed from blocks of neutral faces in frontal view through increasing variations in view and expression. Whereas the control task did not change perception, training improved perceptual sensitivity for the trained faces and generalized to new untrained expressions and views of those faces. There was also a significant transfer to new faces. Benefits were maintained over a 3-month period. Training efficacy was greater for those with more perceptual deficits at baseline. We conclude that perceptual learning can lead to persistent improvements in face discrimination in acquired prosopagnosia. This reflects both acquisition of new skills that can be applied to new faces as well as a degree of overlearning of the stimulus set at the level of 3-D expression-invariant representations.

Seeing the eyes in acquired prosopagnosia.

Case reports have suggested that perception of the eye region may be impaired more than that of other facial regions in acquired prosopagnosia. However, it is unclear how frequently this occurs, whether such impairments are specific to a certain anatomic subtype of prosopagnosia, and whether these impairments are related to changes in the scanning of faces. We studied a large cohort of 11 subjects with this rare disorder, who had a variety of occipitotemporal or anterior temporal lesions, both unilateral and bilateral. Lesions were characterized by functional and structural imaging. Subjects performed a perceptual discrimination test in which they had to discriminate changes in feature position, shape, or external contour. Test conditions were manipulated to stress focused or divided attention across the whole face. In a second experiment we recorded eye movements while subjects performed a face memory task. We found that greater impairment for eye processing was more typical of subjects with occipitotemporal lesions than those with anterior temporal lesions. This eye selectivity was evident for both eye position and shape, with no evidence of an upper/lower difference for external contour. A greater impairment for eye processing was more apparent under attentionally more demanding conditions. Despite these perceptual deficits, most subjects showed a normal tendency to scan the eyes more than the mouth. We conclude that occipitotemporal lesions are associated with a partially selective processing loss for eye information and that this deficit may be linked to loss of the right fusiform face area, which has been shown to have activity patterns that emphasize the eye region.

The relationship between visual word and face processing lateralization in the fusiform gyri: A cross-sectional study.

Visual words and faces activate similar networks but with complementary hemispheric asymmetries, faces being lateralized to the right and words to the left. A recent theory proposes that this reflects developmental competition between visual word and face processing. We investigated whether this results in an inverse correlation between the degree of lateralization of visual word and face activation in the fusiform gyri. 26 literate right-handed healthy adults underwent functional MRI with face and word localizers. We derived lateralization indices for cluster size and peak responses for word and face activity in left and right fusiform gyri, and correlated these across subjects. A secondary analysis examined all face- and word-selective voxels in the inferior occipitotemporal cortex. No negative correlations were found. There were positive correlations for the peak MR response between word and face activity within the left hemisphere, and between word activity in the left visual word form area and face activity in the right fusiform face area. The face lateralization index was positively rather than negatively correlated with the word index. In summary, we do not find a complementary relationship between visual word and face lateralization across subjects. The significance of the positive correlations is unclear: some may reflect the influences of general factors such as attention, but others may point to other factors that influence lateralization of function.

Getting lost: Topographic skills in acquired and developmental prosopagnosia.

Previous studies report that acquired prosopagnosia is frequently associated with topographic disorientation. Whether this is associated with a specific anatomic subtype of prosopagnosia, how frequently it is seen with the developmental variant, and what specific topographic function is impaired to account for this problem are not known. We studied ten subjects with acquired prosopagnosia from either occipitotemporal or anterior temporal (AT) lesions and seven with developmental prosopagnosia. Subjects were given a battery of topographic tests, including house and scene recognition, the road map test, a test of cognitive map formation, and a standardized self-report questionnaire. House and/or scene recognition were frequently impaired after either occipitotemporal or AT lesions in acquired prosopagnosia. Subjects with occipitotemporal lesions were also impaired in cognitive map formation: an overlap analysis identified right fusiform and parahippocampal gyri as a likely correlate. Only one subject with acquired prosopagnosia had mild difficulty with directional orientation on the road map test. Only one subject with developmental prosopagnosia had difficulty with cognitive map formation, and none were impaired on the other tests. Scores for house and scene recognition correlated most strongly with the results of the questionnaire. We conclude that topographic disorientation in acquired prosopagnosia reflects impaired place recognition, with a contribution from poor cognitive map formation when there is occipitotemporal damage. Topographic impairments are less frequent in developmental prosopagnosia.

Voice Recognition in Face-Blind Patients.

Right or bilateral anterior temporal damage can impair face recognition, but whether this is an associative variant of prosopagnosia or part of a multimodal disorder of person recognition is an unsettled question, with implications for cognitive and neuroanatomic models of person recognition. We assessed voice perception and short-term recognition of recently heard voices in 10 subjects with impaired face recognition acquired after cerebral lesions. All 4 subjects with apperceptive prosopagnosia due to lesions limited to fusiform cortex had intact voice discrimination and recognition. One subject with bilateral fusiform and anterior temporal lesions had a combined apperceptive prosopagnosia and apperceptive phonagnosia, the first such described case. Deficits indicating a multimodal syndrome of person recognition were found only in 2 subjects with bilateral anterior temporal lesions. All 3 subjects with right anterior temporal lesions had normal voice perception and recognition, 2 of whom performed normally on perceptual discrimination of faces. This confirms that such lesions can cause a modality-specific associative prosopagnosia.

The processing of voice identity in developmental prosopagnosia.

BACKGROUND: Developmental prosopagnosia is a disorder of face recognition that is believed to reflect impairments of visual mechanisms. However, voice recognition has rarely been evaluated in developmental prosopagnosia to clarify if it is modality-specific or part of a multi-modal person recognition syndrome. OBJECTIVE: Our goal was to examine whether voice discrimination and/or recognition are impaired in subjects with developmental prosopagnosia. DESIGN/METHODS: 73 healthy controls and 12 subjects with developmental prosopagnosia performed a match-to-sample test of voice discrimination and a test of short-term voice familiarity, as well as a questionnaire about face and voice identification in daily life. RESULTS: Eleven subjects with developmental prosopagnosia scored within the normal range for voice discrimination and voice recognition. One was impaired on discrimination and borderline for recognition, with equivalent scores for face and voice recognition, despite being unaware of voice processing problems. CONCLUSIONS: Most subjects with developmental prosopagnosia are not impaired in short-term voice familiarity, providing evidence that developmental prosopagnosia is usually a modality-specific disorder of face recognition. However, there may be heterogeneity, with a minority having additional voice processing deficits. Objective tests of voice recognition should be integrated into the diagnostic evaluation of this disorder to distinguish it from a multi-modal person recognition syndrome.

Temporal dynamics of the face familiarity effect: bootstrap analysis of single-subject event-related potential data.

Prior event-related potential studies using group statistics within a priori selected time windows have yielded conflicting results about familiarity effects in face processing. Our goal was to evaluate the temporal dynamics of the familiarity effect at all time points at the single-subject level. Ten subjects were shown faces of anonymous people or celebrities. Individual results were analysed using a point-by-point bootstrap analysis. While familiarity effects were less consistent at later epochs, all subjects showed them between 130 and 195 ms in occipitotemporal electrodes. However, the relation between the time course of familiarity effects and the peak latency of the N170 was variable. We concluded that familiarity effects between 130 and 195 ms are robust and can be shown in single subjects. The variability of their relation to the timing of the N170 potential may lead to underestimation of familiarity effects in studies that use group-based statistics.

Word and text processing in acquired prosopagnosia.

OBJECTIVE: A novel hypothesis of object recognition asserts that multiple regions are engaged in processing an object type, and that cerebral regions participate in processing multiple types of objects. In particular, for high-level expert processing, it proposes shared rather than dedicated resources for word and face perception, and predicts that prosopagnosic subjects would have minor deficits in visual word processing, and alexic subjects would have subtle impairments in face perception. In this study, we evaluated whether prosopagnosic subjects had deficits in processing either the word content or the style of visual text. METHODS: Eleven prosopagnosic subjects, 6 with unilateral right lesions and 5 with bilateral lesions, participated. In the first study, we evaluated their word length effect in reading single words. In the second study, we assessed their time and accuracy for sorting text by word content independent of style, and for sorting text by handwriting or font style independent of word content. RESULTS: Only subjects with bilateral lesions showed mildly elevated word length effects. Subjects were not slowed in sorting text by word content, but were nearly uniformly impaired in accuracy for sorting text by style. INTERPRETATION: Our results show that prosopagnosic subjects are impaired not only in face recognition but also in perceiving stylistic aspects of text. This supports a modified version of the many-to-many hypothesis that incorporates hemispheric specialization for processing different aspects of visual text.

Acquired prosopagnosia: structural basis and processing impairments.

Cognitive models propose a hierarchy of parallel processing stages in face perception, and functional neuroimaging shows a network of regions involved in face processing. Reflecting this, acquired prosopagnosia is not a single entity but a family of disorders with different anatomic lesions and different functional deficits. One classic distinction is between an apperceptive variant, in which there is impaired perception of facial structure, and an associative/amnestic variant, in which perception is relatively intact, with subsequent problems matching perception to facial memories, because of either disconnection or loss of those memories. These disorders also have to be distinguished from people-specific amnesia, a multimodal impairment, and prosop-anomia, in which familiarity with faces is preserved but access to names is disrupted. These different disorders can be conceived as specific deficits at different processing stages in cognitive models, and suggests that these functional stages may have distinct neuroanatomic substrates. It remains to be seen whether a similar anatomic and functional variability is present in developmental prosopagnosia.

Neuroanatomic correlates of the feature-salience hierarchy in face processing: an fMRI -adaptation study.

Previous fMRI studies suggest that faces are represented holistically in human face processing regions. On the other hand, behavioral studies have also shown that some facial features are more salient than others for face recognition: the neural basis of this feature-salience hierarchy is not known. We used fMRI-adaptation together with a behavioral discrimination task and an ideal observer analysis to ask (1) whether different face parts contribute different amounts to the neural signal in face responsive regions, and (2) whether this response correlates more with the behavioral performance of human subjects or with the physical properties of the face stimuli. Twenty-three subjects performed a same/different discrimination experiment to characterize their ability to detect changes to different face parts. The same subjects underwent an fMRI-adaptation study, in which limited portions of the faces were repeated or changed between alternating stimuli. The behavioral study showed high efficiency in identity discrimination when the whole face, top half, or eyes changed, and low efficiency when the bottom half, nose, or mouth changed. During fMRI, there was a release of adaptation in the right and left fusiform face area (FFA) with changes to the whole face, top face-half, or the eyes. Changes to the bottom half, nose or mouth did not result in a significant release of adaptation in the right FFA, although bottom-half changes resulted in a release of adaptation in the left FFA. Adaptation in the right and left FFA and the right pSTS was correlated with human perceptual efficiency but not with ideal observer measures of the physical image differences between face parts. The feature-salience hierarchy of human face perception is therefore reflected in the activity in the right and left FFA and right pSTS, further supporting the key role of these structures in our perceptual experience of faces.

Spatial relationships between GABAergic and glutamatergic synapses on the dendrites of distinct types of mouse retinal ganglion cells across development.

Neuronal output requires a concerted balance between excitatory and inhibitory (I/E) input. Like other circuits, inhibitory synaptogenesis in the retina precedes excitatory synaptogenesis. How then do neurons attain their mature balance of I/E ratios despite temporal offset in synaptogenesis? To directly compare the development of glutamatergic and GABAergic synapses onto the same cell, we biolistically transfected retinal ganglion cells (RGCs) with PSD95CFP, a marker of glutamatergic postsynaptic sites, in transgenic Thy1-YFPγ2 mice in which GABAA receptors are fluorescently tagged. We mapped YFPγ2 and PSD95CFP puncta distributions on three RGC types at postnatal day P12, shortly before eye opening, and at P21 when robust light responses in RGCs are present. The mature IGABA/E ratios varied among ON-Sustained (S) A-type, OFF-S A-type, and bistratified direction selective (DS) RGCs. These ratios were attained at different rates, before eye-opening for ON-S and OFF-S A-type, and after eye-opening for DS RGCs. At both ages examined, the IGABA/E ratio was uniform across the arbors of the three RGC types. Furthermore, measurements of the distances between neighboring PSD95CFP and YFPγ2 puncta on RGC dendrites indicate that their local relationship is established early in development, and cannot be predicted by random organization. These close spatial associations between glutamatergic and GABAergic postsynaptic sites appear to represent local synaptic arrangements revealed by correlative light and EM reconstructions of a single RGC's dendrites. Thus, although RGC types have different IGABA/E ratios and establish these ratios at separate rates, the local relationship between excitatory and inhibitory inputs appear similarly constrained across the RGC types studied.

The anatomic basis of the right face-selective N170 IN acquired prosopagnosia: a combined ERP/fMRI study.

The N170 waveform is larger over posterior temporal cortex when healthy subjects view faces than when they view other objects. Source analyses have produced mixed results regarding whether this effect originates in the fusiform face area (FFA), lateral occipital cortex, or superior temporal sulcus (STS), components of the core face network. In a complementary approach, we assessed the face-selectivity of the right N170 in five patients with acquired prosopagnosia, who also underwent structural and functional magnetic resonance imaging. We used a non-parametric bootstrap procedure to perform single-subject analyses, which reliably confirmed N170 face-selectivity in each of 10 control subjects. Anterior temporal lesions that spared the core face network did not affect the face-selectivity of the N170. A face-selective N170 was also present in another subject who had lost only the right FFA. However, face-selectivity was absent in two patients with lesions that eliminated the occipital face area (OFA) and FFA, sparing only the STS. Thus while the right FFA is not necessary for the face-selectivity of the N170, neither is the STS sufficient. We conclude that the face-selective N170 in prosopagnosia requires residual function of at least two components of the core face-processing network.

LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development.

Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin-1beta lacking an insert at splice site 4 (-S4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexins 1, 2, and 3 beta but not alpha variants, regardless of insert at splice site 4, LRRTM2 binds to neurexins 1, 2, and 3 alpha and beta variants specifically lacking an insert at splice site 4. We further show that this binding code is conserved in LRRTM1, the family member linked to schizophrenia and handedness, and that the code is functional in a coculture hemisynapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTM2. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin-1beta (-S4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. Thus, we propose a synaptic code hypothesis suggesting that neurexins are master regulators of the cooperative activities of LRRTMs and neuroligins.

The pore helix dipole has a minor role in inward rectifier channel function.

Ion channels lower the energetic barrier for ion passage across cell membranes and enable the generation of bioelectricity. Electrostatic interactions between permeant ions and channel pore helix dipoles have been proposed as a general mechanism for facilitating ion passage. Here, using genetic selections to probe interactions of an exemplar potassium channel blocker, barium, with the inward rectifier Kir2.1, we identify mutants bearing positively charged residues in the potassium channel signature sequence at the pore helix C terminus. We show that these channels are functional, selective, resistant to barium block, and have minimally altered conductance properties. Both the experimental data and model calculations indicate that barium resistance originates from electrostatics. We demonstrate that potassium channel function is remarkably unperturbed when positive charges occur near the permeant ions at a location that should counteract pore helix electrostatic effects. Thus, contrary to accepted models, the pore helix dipole seems to be a minor factor in potassium channel permeation.