Immunohistochemical field parcellation of the human hippocampus along its antero-posterior axis.

The primate hippocampus includes the dentate gyrus, cornu ammonis (CA), and subiculum. CA is subdivided into four fields (CA1-CA3, plus CA3h/hilus of the dentate gyrus) with specific pyramidal cell morphology and connections. Work in non-human mammals has shown that hippocampal connectivity is precisely patterned both in the laminar and longitudinal axes. One of the main handicaps in the study of neuropathological semiology in the human hippocampus is the lack of clear laminar and longitudinal borders. The aim of this study was to explore a histochemical segmentation of the adult human hippocampus, integrating field (medio-lateral), laminar, and anteroposterior longitudinal patterning. We provide criteria for head-body-tail field and subfield parcellation of the human hippocampus based on immunodetection of Rabphilin3a (Rph3a), Purkinje-cell protein 4 (PCP4), Chromogranin A and Regulation of G protein signaling-14 (RGS-14). Notably, Rph3a and PCP4 allow to identify the border between CA3 and CA2, while Chromogranin A and RGS-14 give specific staining of CA2. We also provide novel histological data about the composition of human-specific regions of the anterior and posterior hippocampus. The data are given with stereotaxic coordinates along the longitudinal axis. This study provides novel insights for a detailed region-specific parcellation of the human hippocampus useful for human brain imaging and neuropathology.

Integrated laboratory classes to learn physiology in a psychology degree: impact on student learning and experience.

Physiology is a fundamental discipline to be studied in most Health Science studies including Psychology. Physiology content is perceived by students as rather difficult, who may lack vision on how to relate it with their professional training. Therefore, identifying novel active and more engaging pedagogical strategies for teaching physiology to psychology students may help to fill this gap. In this pilot study, we used the PBL methodology developed around a clinical case to evaluate psychology students' experience and learning in two laboratory classes modalities. The aim of this study was to compare the undergraduates' preference for laboratory classes taught either independently (cohort 1, n = 87 students) or integrated into the PBL-oriented clinical case (cohort 2, n = 92 students) for which laboratory classes were transformed into Integrated Laboratory Classes (ILCs). The students' academic performance was also evaluated to look for quantitative differences between cohorts. We found similar overall academic scores for the Physiology course between cohorts. Interestingly, when we compared the academic scores obtained in the theoretical content from each cohort, we found a significant improvement (p < 0.05) in cohort 2 where the students achieved better results as compared to cohort 1. A subset of students was asked to fill a questionnaire assessment on their experience and found that 78.9% of them preferred integrated laboratory classes over laboratory classes alone. They consistently reported a better understanding of the theoretical content and the value they gave to ILCs for learning. In conclusion, our pilot study suggests that integrating laboratory classes into PBL-oriented clinical contexts help to retain core physiology contents and it can be considered as an engaging learning activity worth implementing in Psychology teaching.

Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice.

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY+ cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood.

Work station learning activities (WSLA) through the ICAP framework: a qualitative study.

BACKGROUND: Engaging, student-centered active learning activities, such as team-based learning (TBL) and laboratory practices, is beneficial to integrate knowledge, particularly in Medicine degree. Previously, we designed and implemented workstation learning activities (WSLA) inspired by TBL, which proved effective for learning requiring higher-order thinking skills. We now hypothesize that WSLA may also have the potential to be framed into a theoretical model that stratifies learning into interactive, constructive, active and passive modes (ICAP hypothesis). METHODS: An interpretive qualitative research study was conducted to evaluate this idea. Semi-structured interviews were conducted with students enrolled in health science programs after WSLA sessions, consisting of a series of activities accompanying a traditional lecture. Interviews were analyzed according to a deductive approach. Theoretical themes and subthemes driving the analysis were organized around the ICAP modes: passive, active, constructive, and interactive. An inductive approach was applied to provide additional insights. RESULTS: Students valued preparatory lectures as well as corresponding WSLA activities as highly motivating, especially for the ability to integrate concepts. Although previous research shows that not all activities require high levels of cognitive engagement, students appreciated the opportunity the WSLA provided to discuss and clarify concepts as a group. Furthermore, feedback from professors and peers was highly appreciated, and helped students to construct new knowledge. CONCLUSION: In this work, by focusing in understanding the student's experience, we have evaluated for the first time the WSLA approach in relation to the ICAP model. We found that not only the activity type determines the learning mode, but also the environment accompanying WSLA is a determining factor. Our findings can guide future development of the WSLA approach, which represents an interactive learning methodology with strong potential within the ICAP framework. TRIAL REGISTRATION: Not applicable.

Forcing a change: a learn-by-doing workshop on circadian rhythms to understand the complexities of human physiology.

Physiology is an integrative science that requires an understanding of the organism as a whole to acquire a deep comprehension of its functions and avoid misconceptions that may impair further learning. Thus it is necessary to develop resources that promote the integrative vision that Physiology requires. Chronobiology is a challenging discipline and one of the least addressed concepts in Physiology curricula. The activity here presented proposes a workshop with a theoretical-practical perspective in the context of the Neuroscience Conferences held annually at our university. All conference presentations are neuroscience-related topics, in combination with practical activities, some of them analyzing variables of the students themselves. We chose to assess this informal teaching scenario to involve the students with a scientific perspective while learning and hoping to increase their appreciation for different topics related to neuroscience. Specifically for this activity on chronobiology, the evaluation was carried out via a survey study including quantitative and qualitative questions and semistructured personal interviews. In general, the results reveal a very positive opinion from students regarding aspects such as the teaching methodology, the organization before and during the activity or the added value of the experience for their future professional performance. Some of the students stated they were more aware of the importance of their circadian system and even changed some of their personal daily routines after the activity. Such positive feedback encourages us to continue working in this theoretical-practical format in the future, as it contributes to improving students' perception of their own learning.

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis.

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.

Quantitative and qualitative evaluation of a learning model based on workstation activities.

BACKGROUND: Moving towards a horizontal and vertical integrated curriculum, Work-Station Learning Activities (WSLA) were designed and implemented as a new learning instrument. Here, we aim to evaluate whether and how this specific learning model affects academic performance. To better understand how it is received by medical students, a mixed methods research study was conducted. METHODS: In the quantitative strand, two cohorts of first year students were compared: academic year 2015-2016 n = 320 with no exposure to WSLA, and academic year 2016-2017 n = 336 with WSLA. Learning objectives at different levels of Bloom's taxonomy were identified and performance evaluated from multiple-choice questions. In the qualitative strand, a total of six students were purposely selected considering academic performance and motivation, and submitted to semistructured interviews. RESULTS: Performance at both cohorts for learning objectives at lower levels of Bloom's taxonomy was similar (38.8 vs. 39.0%; p = 0.955). In contrast, students in the WSLA group outperformed significantly those not exposed for learning objectives involving upper levels (68.5 vs. 54.2%; p <0.001). A multivariate analysis confirmed that the probability of mastering the second (more complex) objective is 1.64 times higher in students with WSLA methodology (OR 95% CI, 1.15-2.34; p = 0.007) than with traditional methodology. In the interviews, students perceived the clinical scenario of WSLA as a motivator and recognized this methodology as a more constructive framework for understanding of complicated concepts. CONCLUSIONS: In summary, our mixed methods research supports WSLA as a strategy that promotes deep learning and has a positive impact on academic performance for learning objectives involving higher order thinking skills in medical curricula.

Liderando el cambio: hacia un currículo integrado para ciencias biomédicas. Experiencia de la Universidad Europea de Madrid / Leading change: moving towards an integrated curriculum suitable for biomedical sciences. Experience from Universidad Europea de Madrid

Las ciencias biomédicas han experimentado una gran revolución en un corto período. Este avance es posible a través del estudio continuado de los mecanismos moleculares, genéticos y fisiológicos de los procesos biológicos, y ello contribuye a una mejor comprensión del funcionamiento normal de nuestro cuerpo y establece el conocimiento de las bases de la patología. Esto implica que los profesionales de ciencias de la salud deben desarrollar competencias y capacidades especiales que les permitan establecer nexos dinámicos entre las ciencias básicas y su práctica profesional. El diseño curricular más adecuado para la formación en estas competencias y capacidades se logra a través del currículo integrado. El aprendizaje integrado es un proceso centrado en el alumno, mediante el cual se adquieren conocimientos de manera flexible e individualizada a largo plazo. En la Universidad Europea de Madrid hemos afrontado esta nueva necesidad utilizando un modelo de aprendizaje integrado de materias básicas indicado para abordar la integración curricular progresiva, y que hemos denominado WSLA (Work Stations Learning Activities). Se basa en una modificación del aprendizaje basado en equipos adaptada a las directrices europeas y españolas, especialmente indicada para los grados de ciencias de la salud. Utilizando el modelo WSLA podemos crear módulos de actividades de aprendizaje integrado adaptables a distintas situaciones, desde clases magistrales hasta gamificación o prácticas de laboratorio. Proponemos nuestro modelo WSLA como una opción flexible y escalable para adoptar la integración de manera escalonada como paso previo a la integración curricular completa

Biomedical sciences have faced a strong developmental shift in a short period of time. This advance has been boosted by the study of the molecular, genetic and physiological mechanisms of the biological processes. This has a direct effect on the better understanding of the normal functioning of our body and establishes the bases of pathology knowledge. Thus, health science professionals must develop new skills and abilities that allow them to establish links between basic sciences and their professional practice. The most appropriate curricular design for competency and capacity building is achieved through the integrated curriculum. Integrated learning is a student-centered process, through which knowledge is developed lifelong in a flexible and individualized manner. At the Universidad Europea de Madrid we have faced new demands by using a model of integrated learning of basic subjects especially suitable to achieve progressive curricular integration. We have named this new model WSLA (Work Stations Learning Activities) and it is based on a modification of the team based learning adapted to the European and Spanish guidelines especially indicated for the Degrees of Health Sciences. Using the WSLA model different modules of integrated learning activities can be created and adapted to different situations, including master classes, gamification or laboratory practices. We propose our WSLA model as a scalable and flexible option to adopt the stepwise integration as a stage prior to the complete curricular integration

Evaluation of participatory teaching methods in undergraduate medical students' learning along the first academic courses.

The European Higher Education Area (EHEA) is an opportunity to redesign medical education. Academic training is now focused on acquiring not only knowledge, but also those competencies critical to face complex professional scenarios. Together with re-evaluating traditional teaching methods, EHEA has forced a technological shift in the way we teach. By critically assessing the impact of novel teaching methodologies, we can better define biomedical education demands. Here, we address this question on a sample of medical students instructed in basic subjects along the first two academic courses. Two hundred and one medical students participated in the study (n = 128 first year, n = 73 second year). Quantitative (conventional survey statistics) and qualitative (open coding) approaches were combined to analyze data from surveys, confidential questionnaires, semi-structured interviews and open discussion. First year medical students rated more positively the use of participatory methodologies than second year students. A major drawback is detected in the perceived workload. Active teaching methodologies show a strong reliance on their time of implementation for medical students, a key aspect to be considered in the design of integrative participatory curricula along the first academic courses.

Work station learning activities: a flexible and scalable instrument for integrating across basic subjects in biomedical education.

BACKGROUND: Establishing innovative teaching programs in biomedical education involves dealing with several national and supra-national (i.e. European) regulations as well as with new pedagogical and demographic demands. We aimed to develop and validate a suitable instrument to integrate activities across preclinical years in all Health Science Degrees while meeting requirements of national quality agencies. METHODS: The new approach was conceived at two different levels: first, we identified potentially integrative units from different fields according to national learning goals established for each preclinical year (national quality agency regulations). Secondly, we implemented a new instrument that combines active methodologies in Work Station Learning Activities (WSLA), using clinical scenarios as a guiding common thread to instruct students from an integrated perspective. We evaluated students' perception through a Likert-type survey of a total of 118 students enrolled in the first year of the Bachelor's Degree in Medicine. RESULTS: Our model of integrated activities through WSLA is feasible, scalable and manageable with large groups of students and a minimum number of instructors, two major limitations in many medical schools. Students' perception of WSLA was positive in overall terms. Seventy nine percent of participants stated that WSLA sessions were more useful than non-integrated activities. Eighty three percent confirmed that the WSLA methodology was effective at integrating concepts covered by different subjects. CONCLUSIONS: The WSLA approach is a flexible and scalable instrument for moving towards integrated curricula, and it can be successfully adapted to teach basic subjects in preclinical years of Health Science degrees. WSLA can be applied to large groups of students in a variety of contexts or environments using clinical cases as connecting threads.

Altered Oscillatory Dynamics of CA1 Parvalbumin Basket Cells during Theta-Gamma Rhythmopathies of Temporal Lobe Epilepsy.

Recent reports in human demonstrate a role of theta-gamma coupling in memory for spatial episodes and a lack of coupling in people experiencing temporal lobe epilepsy, but the mechanisms are unknown. Using multisite silicon probe recordings of epileptic rats engaged in episodic-like object recognition tasks, we sought to evaluate the role of theta-gamma coupling in the absence of epileptiform activities. Our data reveal a specific association between theta-gamma (30-60 Hz) coupling at the proximal stratum radiatum of CA1 and spatial memory deficits. We targeted the microcircuit mechanisms with a novel approach to identify putative interneuronal types in tetrode recordings (parvalbumin basket cells in particular) and validated classification criteria in the epileptic context with neurochemical identification of intracellularly recorded cells. In epileptic rats, putative parvalbumin basket cells fired poorly modulated at the falling theta phase, consistent with weaker inputs from Schaffer collaterals and attenuated gamma oscillations, as evaluated by theta-phase decomposition of current-source density signals. We propose that theta-gamma interneuronal rhythmopathies of the temporal lobe are intimately related to episodic memory dysfunction in this condition.

Proximodistal structure of theta coordination in the dorsal hippocampus of epileptic rats.

Coherent neuronal activity in the hippocampal-entorhinal circuit is a critical mechanism for episodic memory function, which is typically impaired in temporal lobe epilepsy. To better understand how this mechanism is implemented and degraded in this condition, we used normal and epileptic rats to examine theta activity accompanying active exploration. Assisted by multisite recordings of local field potentials (LFPs) and layer-specific profiling of input pathways, we provide detailed quantification of the proximodistal coherence of theta activity in the dorsal hippocampus of these animals. Normal rats showed stronger coordination between the temporoammonic and perforant entorhinal inputs (measured from lamina-specific current source density signals) at proximal locations, i.e., closer to CA3; while epileptic rats exhibited stronger interactions at distal locations, i.e., closer to subiculum. This opposing trend in epileptic rats was associated with the reorganization of the temporoammonic and perforant pathways that accompany hippocampal sclerosis, the pathological hallmark of this disease. In addition to this connectivity constraint, we discovered that the appropriate timing between entorhinal inputs arriving over several theta cycles at the proximal and distal ends of the dorsal hippocampus was impaired in epileptic rats. Computational reconstruction of LFP signals predicted that restoring timing variability has a major impact on repairing theta coherence. This manipulation, when tested pharmacologically via systemic administration of group III mGluR antagonists, successfully re-established theta coordination of LFPs in epileptic rats. Thus, proximodistal organization of entorhinal inputs is instrumental in temporal lobe physiology and a candidate mechanism to study cognitive comorbidities of temporal lobe epilepsy.

Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations.

Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.

Epileptic seizures in diffuse low-grade gliomas in adults.

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

SU-8 based microprobes for simultaneous neural depth recording and drug delivery in the brain.

While novel influential concepts in neuroscience bring the focus to local activities generated within a few tens of cubic micrometers in the brain, we are still devoid of appropriate tools to record and manipulate pharmacologically neuronal activity at this fine scale. Here we designed, fabricated and encapsulated microprobes for simultaneous depth recording and drug delivery using exclusively the polymer SU-8 as structural material. A tetrode- and linear-like electrode patterning was combined for the first time with single and double fluidic microchannels for independent drug delivery. The device was tested experimentally using the in vivo anesthetized rat preparation. Both probe types successfully recorded detailed spatiotemporal features of local field potentials and single-cell activity at a resolution never attained before with integrated fluidic probes. Drug delivery was achieved with high spatial and temporal precision in a range from tens of nanoliters to a few microliters, as confirmed histologically. These technological advancements will foster a wide range of neural applications aimed at simultaneous monitoring of brain activity and delivery at a very precise micrometer scale.

Systemic injection of kainic acid differently affects LTP magnitude depending on its epileptogenic efficiency.

Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72-85% rats). A group of rats were resistant to develop SE (15-28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals' performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency.

To be or not to be: the importance of attendance in integrated physiology teaching using non-traditional approaches.

BACKGROUND: There is increasing use of non-traditional methods like problem-based learning, team-working and several other active-learning techniques in Physiology teaching. While several studies have investigated the impact of class attendance on the academic performance in traditional teaching, there is limited information regarding whether the new modalities are especially sensible to this factor. METHODS: Here, we performed a comparative study between a control group receiving information through traditional methods and an experimental group submitted to new methodologies in Physiology teaching. RESULTS: We found that while mean examination scores were similar in the control and the experimental groups, a different picture emerge when data are organized according to four categorical attendance levels. In the experimental group, scores were not different between the 1st and the 2nd exams (P = 0.429) nor between the 2nd and the 3rd exams (P = 0.225) for students that never or poorly attend classes, in contrast to the control group (P < 0.001). A score difference between attending students versus the absentees was maximal in the experimental versus the control group all along the different exams and in the final score. CONCLUSION: We suggest that class attendance is critical for learning using non-traditional methods.

Hippocampal-dependent spatial memory in the water maze is preserved in an experimental model of temporal lobe epilepsy in rats.

Cognitive impairment is a major concern in temporal lobe epilepsy (TLE). While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se.

Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus.

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.