NMDARs in granule cells contribute to parallel fiber-Purkinje cell synaptic plasticity and motor learning.

Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.

T-type channel blockade impairs long-term potentiation at the parallel fiber-Purkinje cell synapse and cerebellar learning.

CaV3.1 T-type channels are abundant at the cerebellar synapse between parallel fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca(2+) carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that CaV3.1 channels are required for long-term potentiation at parallel fiber-Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for CaV3.1 channels in cerebellar learning.

Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule.

The detailed characterization of synaptic plasticity has led to the replacement of simple Hebbian rules by more complex rules depending on the order of presynaptic and postsynaptic action potentials. Here, we describe a mechanism endowing a plasticity rule with additional computational complexity--a dependence on the pattern of presynaptic action potentials. The classical Hebbian rule is based on detection of conjunctive presynaptic and postsynaptic activity by postsynaptic NMDA receptors, but there is also accumulating evidence for the existence of presynaptic NMDA receptors in several brain structures. Here, we examine the role of presynaptic NMDA receptors in defining the temporal structure of the plasticity rule governing induction of long-term depression (LTD) at the cerebellar parallel fiber-Purkinje cell synapse. We show that multiple presynaptic action potentials at frequencies between 40 Hz and 1 kHz are necessary for LTD induction. We characterize the subtype, kinetics, and role of presynaptic NMDA receptors involved in the induction of LTD, showing how the kinetics of the NR2A subunits expressed by parallel fibers implement a high-pass filter plasticity rule that will selectively attenuate synapses undergoing high-frequency bursts of activity. Depending on the type of NMDA receptor subunit expressed, high-pass filters of different corner frequencies could be implemented at other synapses expressing NMDA autoreceptors.

GluN3A excitatory glycine receptors control adult cortical and amygdalar circuits.

GluN3A is an atypical glycine-binding subunit of NMDA receptors (NMDARs) whose actions in the brain are mostly unknown. Here, we show that the expression of GluN3A subunits controls the excitability of mouse adult cortical and amygdalar circuits via an unusual signaling mechanism involving the formation of excitatory glycine GluN1/GluN3A receptors (eGlyRs) and their tonic activation by extracellular glycine. eGlyRs are mostly extrasynaptic and reside in specific neuronal populations, including the principal cells of the basolateral amygdala (BLA) and SST-positive interneurons (SST-INs) of the neocortex. In the BLA, tonic eGlyR currents are sensitive to fear-conditioning protocols, are subject to neuromodulation by the dopaminergic system, and control the stability of fear memories. In the neocortex, eGlyRs control the in vivo spiking of SST-INs and the behavior-dependent modulation of cortical activity. GluN3A-containing eGlyRs thus represent a novel and widespread signaling modality in the adult brain, with attributes that strikingly depart from those of conventional NMDARs.

Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression.

At the cerebellar synapses between parallel fibers (PFs) and Purkinje cells (PCs), long-term depression (LTD) of the excitatory synaptic current has been assumed to be independent of the N-methyl-D-aspartate (NMDA) receptor activation because PCs lack NMDA receptors. However, we now report that LTD is suppressed by NMDA receptor antagonists that act on presynaptic NMDA receptors of the PFs. This effect is still observed when the input is restricted to a single fiber. Therefore, LTD does not require the spatial integration of multiple inputs. In contrast, it involves a temporal integration, since reliable LTD induction requires the PFs to fire two action potentials in close succession. This implies that LTD will selectively depress the response to a burst of presynaptic action potentials.

Triheteromeric NMDA receptors: from structure to synaptic physiology.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play crucial roles in brain development and synaptic plasticity. They are also therapeutic targets of interest since their dysfunction is associated with multiple neurological and psychiatric disorders. In vivo, NMDARs exist as multiple subtypes that differ in their subunit composition, anatomical distribution, functional properties, as well as signaling capacities. While much is known about diheteromeric NMDARs composed of two GluN1 subunits and two identical GluN2 (or GluN3) subunits, the majority of native NMDARs are triheteromers containing two GluN1 and two different GluN2 (or a combination of GluN2 and GluN3). Knowledge about triheteromeric NMDARs has recently boomed, with the first decoding of their atomic structure and the development of a new methodology allowing selective expression of recombinant triheteromers at the cell-surface without confounding co-expression of diheteromers. Here we review these progresses and highlight the unique attributes of triheteromers. Particular emphasis is put on GluN1/GluN2A/GluN2B triheteromers, presumably the most abundant NMDARs in the adult forebrain and critical actors of synaptic plasticity. Better understanding triheteromeric NMDAR structure and function is of major interest for brain physiology and drug discovery.

Burst-Dependent Bidirectional Plasticity in the Cerebellum Is Driven by Presynaptic NMDA Receptors.

Numerous studies have shown that cerebellar function is related to the plasticity at the synapses between parallel fibers and Purkinje cells. How specific input patterns determine plasticity outcomes, as well as the biophysics underlying plasticity of these synapses, remain unclear. Here, we characterize the patterns of activity that lead to postsynaptically expressed LTP using both in vivo and in vitro experiments. Similar to the requirements of LTD, we find that high-frequency bursts are necessary to trigger LTP and that this burst-dependent plasticity depends on presynaptic NMDA receptors and nitric oxide (NO) signaling. We provide direct evidence for calcium entry through presynaptic NMDA receptors in a subpopulation of parallel fiber varicosities. Finally, we develop and experimentally verify a mechanistic plasticity model based on NO and calcium signaling. The model reproduces plasticity outcomes from data and predicts the effect of arbitrary patterns of synaptic inputs on Purkinje cells, thereby providing a unified description of plasticity.

Reallocation of Olfactory Cajal-Retzius Cells Shapes Neocortex Architecture.

The neocortex undergoes extensive developmental growth, but how its architecture adapts to expansion remains largely unknown. Here, we investigated how early born Cajal-Retzius (CR) neurons, which regulate the assembly of cortical circuits, maintain a dense superficial distribution in the growing neocortex. We found that CR cell density is sustained by an activity-dependent importation of olfactory CR cells, which migrate into the neocortex after they have acted as axonal guidepost cells in the olfactory system. Furthermore, using mouse genetics, we showed that CR cell density severely affects the architecture of layer 1, a key site of input integration for neocortical networks, leading to an excitation/inhibition ratio imbalance. Our study reveals that neurons reenter migration several days after their initial positioning, thereby performing sequential developmental roles in olfactory cortex and neocortex. This atypical process is essential to regulate CR cell density during growth, which in turn ensures the correct wiring of neocortical circuitry. VIDEO ABSTRACT.

Properties and molecular identity of NMDA receptors at synaptic and non-synaptic inputs in cerebellar molecular layer interneurons.

N-methyl-D-aspartate receptors (NMDARs) in cerebellar molecular layer interneurons (MLIs) are expressed and activated in unusual ways: at parallel fibre (PF) synapses they are only recruited by repetitive stimuli, suggesting an extrasynaptic location, whereas their activation by climbing fibre is purely mediated by spillover. NMDARs are thought to play an important role in plasticity at different levels of the cerebellar circuitry. Evaluation of the location, functional properties and physiological roles of NMDARs will be facilitated by knowledge of the NMDAR isoforms recruited. Here we show that MLI-NMDARs activated by both PF and climbing fibre inputs have similar kinetics and contain GluN2B but not GluN2A subunits. On the other hand, no evidence was found of functional NMDARs in the axons of MLIs. At the PF-Purkinje cell (PF-PC) synapse, the activation of GluN2A-containing NMDARs has been shown to be necessary for the induction of long-term depression (LTD). Our results therefore provide a clear distinction between the NMDARs located on MLIs and those involved in plasticity at PF-PC synapses.

Insight, psychopathology, and interpersonal relationships in schizophrenia.

Insight of patients with schizophrenia seems to be a complex phenomenon that includes elements of a psychological, psychopathological, neurocognitive, and interactional nature. The purpose of this research was to study two of these areas (psychopathology and interpersonal relationships) in order to determine their influence on insight and their interrelation. Eighty-two outpatients fulfilling DSM-IV criteria for schizophrenia were studied using the Schedule for the Assessment of Insight (SAI), the Positive and Negative Syndrome Scale (PANSS), and the Social Cognitions and Object Relations Scale (SCORS). Bivariate correlations and multiple regression tests were performed. The positive component of the PANSS and the understanding of social causality (SCORS) appeared as the most significant variables related to level of insight. Positive symptoms were inversely related to insight, whereas understanding of social causality was directly associated with an appropriate awareness of illness. These results support the idea that insight is a complex and multidimensional phenomenon. In this respect, the study of the psychopathological dimension of insight should be accompanied by the consideration of interactional and social factors, because awareness of illness can be considered ultimately as an index of concordance between patients' views of the illness and cultural standards regarding mental disorders.

Zinc dynamics and action at excitatory synapses.

Decades after the discovery that ionic zinc is present at high levels in glutamatergic synaptic vesicles, where, when, and how much zinc is released during synaptic activity remains highly controversial. Here we provide a quantitative assessment of zinc dynamics in the synaptic cleft and clarify its role in the regulation of excitatory neurotransmission by combining synaptic recordings from mice deficient for zinc signaling with Monte Carlo simulations. Ambient extracellular zinc levels are too low for tonic occupation of the GluN2A-specific nanomolar zinc sites on NMDA receptors (NMDARs). However, following short trains of physiologically relevant synaptic stimuli, zinc transiently rises in the cleft and selectively inhibits postsynaptic GluN2A-NMDARs, causing changes in synaptic integration and plasticity. Our work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses. By specifically moderating GluN2A-NMDAR signaling, zinc acts as a widespread activity-dependent regulator of neuronal circuits.

Single myelin fiber imaging in living rodents without labeling by deep optical coherence microscopy.

Myelin sheath disruption is responsible for multiple neuropathies in the central and peripheral nervous system. Myelin imaging has thus become an important diagnosis tool. However, in vivo imaging has been limited to either low-resolution techniques unable to resolve individual fibers or to low-penetration imaging of single fibers, which cannot provide quantitative information about large volumes of tissue, as required for diagnostic purposes. Here, we perform myelin imaging without labeling and at micron-scale resolution with >300-µm penetration depth on living rodents. This was achieved with a prototype [termed deep optical coherence microscopy (deep-OCM)] of a high-numerical aperture infrared full-field optical coherence microscope, which includes aberration correction for the compensation of refractive index mismatch and high-frame-rate interferometric measurements. We were able to measure the density of individual myelinated fibers in the rat cortex over a large volume of gray matter. In the peripheral nervous system, deep-OCM allows, after minor surgery, in situ imaging of single myelinated fibers over a large fraction of the sciatic nerve. This allows quantitative comparison of normal and Krox20 mutant mice, in which myelination in the peripheral nervous system is impaired. This opens promising perspectives for myelin chronic imaging in demyelinating diseases and for minimally invasive medical diagnosis.

A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene.

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.

[Cutaneous myiasis over tumor-lesions: presentation of three cases]. / Miasis cutáneas sobre lesiones tumorales: presentación de tres casos.

We report three cases of myiasis in patients with tumor-lesions. The first patient, a 54-year-old male, presented with laryngeal carcinoma with extensive local involvement, forming a large tumorous mass on the front of the neck that had been irradiated, where several active larvae were seen. The other two patients, females aged 101 and 87 years, respectively, presented with skin tumors on the scalp and face, and several active larvae could be seen in these tumors. After microbiological examination of the larvae removed, the species in the first case was identified as Chrysomya, while the species in the other two cases was Sarcophaga. Several risk factors for developing myiasis have been described, such as advanced age, poor hygiene, diabetes mellitus, venous insufficiency, etc. These manifestations are self-limited, but in most cases treatment is necessary. This consists of cleaning and mechanical removal of visible larvae, with or without occlusion methods.

[Topical treatment of melanoma skin metastases with imiquimod]. / Tratamiento tópico de las metástasis cutáneas de melanoma con imiquimod.

The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.

[Herpetiform pemphigus associated with esophageal carcinoma]. / Pénfigo herpetiforme asociado a carcinoma de esófago.

We present the case of a 63-year-old woman with herpetiform pemphigus and disseminated esophageal carcinoma which began to manifest themselves simultaneously. Some cases of herpetiform pemphigus associated with neoplasms have previously been reported, but these have primarily been bronchopulmonary. The association of any type of pemphigus with esophageal cancer is very infrequent. We should be alert to the infrequent varieties of pemphigus and atypical bullous diseases, because they sometimes do not meet the diagnostic criteria of paraneoplastic pemphigus, but are the first manifestation of an underlying neoplasm.

Psicopatología en pacientes con obesidad mórbida poscirugía gástrica / Psychopathology in patients with morbid obesity after gastric surgery

Se sabe que la obesidad mórbida es una enfermedad compleja que puede deberse a factores biológicos, psicológicos o sociales, además de estar influida por determinados factores metabólicos y de comportamiento. Se analizó la psicopatología de un grupo compuesto por 100 pacientes (85 mujeres, 15 hombres) con obesidad mórbida, que habían recibido tratamiento quirúrgico de restricción gástrica (gastroplastia vertical bandeada) para perder peso. Cada paciente completó la Symptom Check List- 90-R (SCL-90-R) 18 meses después de la cirugía; 40 (40(por ciento) cumplieron criterios CIE-10 de patología psiquiátrica. Se determinaron los diagnósticos psiquiátricos más frecuentes: trastornos afectivos, de ansiedad, alimentarios (trastorno por atracón, anorexia nerviosa, bulimia nerviosa) y dependencia de alcohol. Se precisó la conflictiva de pareja en el 50(por ciento) de las pacientes con patología psiquiátrica. El estudio de regresión logística ha mostrado relación entre la existencia de patología psiquiátrica y las escalas de depresión, ansiedad, hostilidad e índice de severidad general de la SCL-90-R. No se halló relación entre la edad de inicio y la psicopatología detectada. Se comprobó que los pacientes con enfermedad mórbida presentan una importante tasa de patología psiquiátrica y elevados niveles de malestar psicológico y dicho estado se relaciona con el índice de severidad general de la SCL-90R(AU)

It is known that morbid obesity is a complex disease that may be caused by biological, psychological or social factors and that certain metabolic and compartmental factors influence on it. The psychopathology of a group made up of 100 patients (85 women, 15 men) with morbid obesity that had undergone surgical treatment of gastric restriction (vertical banding gastroplasty) to lose weight was analyzed. Each patient completed the Symptom Check List-90-R (SCL-90-R). 18 months after surgery, 40 of them (40 percent) fulfilled the ICD-10 criteria of psychiatric pathology. The most frequent psychiatric diagnoses were determined: affective disturbance, anxiety disorder and food disorder (disturbance due to gluttony, nervous anorexia and nervous bulimia) and alcohol dependence. The conflict of the couple was observed in 50 percent of the patients with psychiatric pathology. The logistic regression study has shown a relationship between the existance of psychiatric pathology and the scales of depression, anxiety, hostility and index of general severity of the SCL-90-R. No relation was found between the age at onset and the detected psychopathology. It was proved that the patients with morbid disease present an important rate of psychiatric pathology and high levels of psychological malaise and such state is related to the index of general severity of the SCL-90-R(AU)

Miasis cutáneas sobre lesiones tumorales: presentación de tres casos / Cutaneous myiasis over tumor-lesions: presentation of three cases

Comunicamos 3 casos de miasis en pacientes con lesiones tumorales. El primer paciente, de 54 años, presentaba un carcinoma laríngeo con gran afectación local que formaba una gran masa tumoral en la cara anterior del cuello, previamente irradiada, donde se visualizaron varias larvas móviles. Las 2 pacientes restantes, de 101 y 87 años, respectivamente, presentaban tumores cutáneos en cuero cabelludo y cara, y en ellos se objetivaron numerosas larvas móviles. El examen microbiológico de las larvas extraídas identificó en el primer caso la especie Chrysomyia y en los otros dos la especie Sarcophaga. Se han descrito una serie de factores de riesgo de adquirir una miasis, como edad avanzada, higiene deficiente, diabetes mellitus, insuficiencia venosa, etc. Estos cuadros son autolimitados, pero en la mayoría de los casos es necesario realizar tratamiento, que consiste en la limpieza y eliminación mecánica de las larvas visibles, asociado o no a métodos de oclusión

We report three cases of myiasis in patients with tumor-lesions. The first patient, a 54-year-old male, presented with laryngeal carcinoma with extensive local involvement, forming a large tumorous mass on the front of the neck that had been irradiated, where several active larvae were seen. The other two patients, females aged 101 and 87 years, respectively, presented with skin tumors on the scalp and face, and several active larvae could be seen in these tumors. After microbiological examination of the larvae removed, the species in the first case was identified as Chrysomyia, while the species in the other two cases was Sarcophaga. Several risk factors for developing myiasis have been described, such as advanced age, poor hygiene, diabetes mellitus, venous insufficiency, etc. These manifestations are self-limited, but in most cases treatment is necessary. This consists of cleaning and mechanical removal of visible larvae, with or without occlusion methods