Early and transitory hypoactivity and olfactory alterations after chronic atrazine exposure in female Sprague-Dawley rats.

Several studies have shown that chronic exposure to the herbicide atrazine (ATR) causes alterations in locomotor activity and markers of the dopaminergic systems of male rats. However, few studies have evaluated the sex-dependent effects of atrazine exposure. The aim of the present study was to evaluate whether chronic ATR exposure causes alterations in behavioral performance and dopaminergic systems of female rats. At weaning, two groups of rats were exposed to 1 or 10 mg ATR/kg body weight daily thorough the food, while the control group received food without ATR for 14 months. Spontaneous locomotor activity was evaluated monthly for 12 months, while anxiety, egocentric and spatial memory, motor coordination, and olfactory function tasks were evaluated between 13 and 14 months of ATR exposure. Tyrosine hydroxylase (TH) and monoamine content in brain tissue were assessed at the end of ATR treatment. Female rats treated with 1 or 10 mg ATR showed vertical hypoactivity compared to the control group only in the first month of ATR exposure. Impairments in olfactory functions were found due to ATR exposure. Nevertheless, no alterations in anxiety, spatial and egocentric memory, or motor coordination tasks were observed, while the levels of TH and dopamine and its metabolites in brain tissue were similar among groups. These results suggest that female rats could present greater sensitivity to the neurotoxic effects of ATR on spontaneous locomotor activity in the early stages of development. However, they are unaffected by chronic ATR exposure later in life compared to male rats. More studies are necessary to unravel the sex-related differences observed after chronic ATR exposure.

Contribution and functional connectivity between cerebrum and cerebellum on sub-lexical and lexical-semantic processing of verbs.

Language comprehension involves both sub-lexical (e.g., phonological) and lexical-semantic processing. We conducted a task using functional magnetic resonance imaging (fMRI) to compare the processing of verbs in these two domains. Additionally, we examined the representation of concrete-motor and abstract-non-motor concepts by including two semantic categories of verbs: motor and mental. The findings indicate that sub-lexical processing during the reading of pseudo-verbs primarily involves the left dorsal stream of the perisylvian network, while lexical-semantic representation during the reading of verbs predominantly engages the ventral stream. According to the embodied or grounded cognition approach, modality-specific mechanisms (such as sensory-motor systems) and the well-established multimodal left perisylvian network contribute to the semantic representation of both concrete and abstract verbs. Our study identified the visual system as a preferential modality-specific system for abstract-mental verbs, which exhibited functional connectivity with the right crus I/lobule VI of the cerebellum. Taken together, these results confirm the dissociation between sub-lexical and lexical-semantic processing and provide neurobiological evidence of functional coupling between specific visual modality regions and the right cerebellum, forming a network that supports the semantic representation of abstract concepts. Further, the results shed light on the underlying mechanisms of semantic processing and contribute to our understanding of how the brain processes abstract concepts.

A novel task to evaluate irony comprehension and its essential elements in Spanish speakers.

An ironic statement transmits the opposite meaning to its literal counterpart and is one of the most complex communicative acts. Thus, it has been proposed to be a good indicator of social communication ability. Prosody and facial expression are two crucial paralinguistic cues that can facilitate the understanding of ironic statements. The primary aim of this study was to create and evaluate a task of irony identification that could be used in neuroimaging studies. We independently evaluated three cues, contextual discrepancy, prosody and facial expression, and selected the best cue that would lead participants in fMRI studies to identify a stimulus as ironic in a reliable way. This process included the design, selection, and comparison of the three cues, all of which have been previously associated with irony detection. The secondary aim was to correlate irony comprehension with specific cognitive functions. Results showed that psycholinguistic properties could differentiate irony from other communicative acts. The contextual discrepancy, prosody, and facial expression were relevant cues that helped detect ironic statements; with contextual discrepancy being the cue that produced the highest classification accuracy and classification time. This task can be used successfully to test irony comprehension in Spanish speakers using the cue of interest. The correlation of irony comprehension with cognitive functions did not yield consistent results. A more heterogeneous sample of participants and a broader battery of tests may be needed to find reliable cognitive correlates of irony comprehension.

What Deception Tasks Used in the Lab Really Do: Systematic Review and Meta-analysis of Ecological Validity of fMRI Deception Tasks.

Interpretation of the neural findings of deception without considering the ecological validity of the experimental tasks could lead to biased conclusions. In this study we classified the experimental tasks according to their inclusion of three essential components required for ecological validity: intention to lie, social interaction and motivation. First, we carried out a systematic review to categorize fMRI deception tasks and to weigh the degree of ecological validity of each one. Second, we performed a meta-analysis to identify if each type of task involves a different neural substrate and to distinguish the neurocognitive contribution of each component of ecological validity essential to deception. We detected six categories of deception tasks. Intention to lie was the component least frequently included, followed by social interaction. Monetary reward was the most frequent motivator. The results of the meta-analysis, including 59 contrasts, revealed that intention to lie is associated with activation in the left lateral occipital cortex (superior division) whereas the left angular gyrus and right inferior frontal gyrus (IFG) are engaged during lying under instructions. Additionally, the right IFG appears to participate in the social aspect of lying including simulated and real interactions. We found no effect of monetary reward in our analysis. Finally, tasks with high ecological validity recruited fewer brain areas (right insular cortex and bilateral anterior cingulate cortex (ACC)) compared to less ecological tasks, perhaps because they are more natural and realistic, and engage a wide network of brain mechanisms, as opposed to specific tasks that demand more centralized processes.

Theory of Mind and Its Elusive Structural Substrate.

Is brain structure related to function? Can one predict the other? These are questions that are still waiting to be answered definitively. In this paper we seek to investigate these questions, in particular, we are interested in the relation between brain structure and theory of mind (ToM). ToM is defined as the ability to attribute mental states to others. Previous studies have observed correlations between performance on ToM tasks, and gray-matter size/volume in dorsomedial prefrontal cortex (dmPFC), temporoparietal junction (TPJ) and precuneus (PCu). Despite these findings, there are concerns about false positive results and replicability issues. In this study we used two different tasks to evaluate ToM, Reading the Mind in the Eyes Test (RMET), and the Short Story Task (SST). Performance in these tasks was correlated to brain anatomy measures including voxel-based morphometry (VBM) and cortical thickness (CT) analysis, from ninety-one neurotypical participants. High-resolution structural brain images were acquired, and whole-brain and region of interest (ROI) analyses were implemented. The analyses did not show statistically significant associations between ToM performance and brain structural measures after correction. Significant associations between performance on ToM tests and a widespread array of regions loosely associated with ToM were observed only for whole brain uncorrected analysis (p < 0.001). These results do not replicate a previous study with neurotypical participants. We tested two different ToM tests, two different softwares for VBM and CT, and we used two samples, one with 91 and a sub-sample with 69 participants. Neither of these conditions made a difference in the results obtained. Consequently, these results suggest that if the population is neurotypical and homogenous, it is unlikely that a reliable association between brain anatomy measures and ToM performance, as measured with these tasks, may be found.

A Quantitative Meta-analysis of Neuroimaging Studies of Pragmatic Language Comprehension: In Search of a Universal Neural Substrate.

Pragmatics may be defined as the ability to communicate by expressing and recognizing intentions. The objective of this meta-analysis was to identify neural substrates for comprehension of pragmatic content in general, as well as the differences between pragmatic forms, and to describe if there is differential recruitment of brain areas according to natural language. This meta-analysis included 48 functional magnetic resonance imaging studies that reported pragmatic versus literal language contrasts. The pragmatic forms were speech acts, metaphors, idioms, and irony. Effect Size-Signed Differential Mapping software was used to calculate the mean for all contrasts as well as for each pragmatic form, and make comparisons among all forms. Due to variations in pragmatic content configuration such as natural language, stimulus modality, and writing systems, these variations were also analyzed with subgroups' analyses. The analyses found a highly reproducible bilateral fronto-temporal and medial prefrontal cortex network for pragmatic comprehension. Each pragmatic form showed a specific convergence pattern within this bilateral network. Natural language analyses showed that fronto-temporal regions were recruited by Germanic languages, while only left frontal areas were recruited by Romance languages, and right medial prefrontal cortex by Japanese. In conclusion, pragmatic language comprehension involves classical language areas in bilateral perisylvian regions, along with the medial prefrontal cortex, an area involved in social cognition. Together, these areas could represent the "pragmatic language network". Nonetheless, when proposing a universal neural substrate for all forms of pragmatic language, the diversity among studies in terms of pragmatic form, and configuration, must be taken into consideration.

Risk-taking, locomotor activity and dopamine levels in the nucleus accumbens and medial prefrontal cortex in male rats treated prenatally with alcohol.

BACKGROUND: Prenatal alcohol exposure (PA) restricted to days 8-20 of rat gestation reduces the activity of the dopaminergic neurons (DA) in the ventral tegmental area (VTA). Hyperactivity and impulsivity have been observed under this treatment; however, it is unknown whether DA levels are affected. Decision-making in risk situations, meanwhile, has been associated with impulsive behavior, but because studies of this phenomenon in animal models are limited, we do not yet know whether PA has any effect. The present study investigated the effects of PA on risk-taking behavior and locomotor activity in pre-pubertal male rats. In addition, DA levels in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) in response to methylphenidate (MP) were assessed. METHODS: Dams were treated with either two daily 3.0-g/kg doses of alcohol or an isocaloric solution, from days 8-20 of gestation. Locomotor activity and risk-taking in pre-pubertal male rats after PA, and DA levels in the NAcc and mPFC after a single dose of MP (5mg/kg), were analyzed. RESULTS: Hyperactivity and increased risk-taking behavior were observed in the rats treated prenatally with alcohol compared to controls. Methylphenidate increased DA levels in the NAcc regardless of prenatal treatment, but significantly higher DA levels were found in the PA group regardless of postnatal treatment with saline or MP. CONCLUSION: The presence of hyperactivity and increased risk-taking behavior after prenatal alcohol treatment is supported. Results suggest that higher DA levels in the rats with PA could be due to a down-regulation of postsynaptic receptors, the desensitization of presynaptic receptors, or a compensatory over-activity of DA neurons in the VTA.

Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice.

Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system.

The herbicide glyphosate causes behavioral changes and alterations in dopaminergic markers in male Sprague-Dawley rat.

Glyphosate (Glyph) is the active ingredient of several herbicide formulations. Reports of Glyph exposure in humans and animal models suggest that it may be neurotoxic. To evaluate the effects of Glyph on the nervous system, male Sprague-Dawley rats were given six intraperitoneal injections of 50, 100, or 150 mg Glyph/kg BW over 2 weeks (three injections/week). We assessed dopaminergic markers and their association with locomotor activity. Repeated exposure to Glyph caused hypoactivity immediately after each injection, and it was also apparent 2 days after the last injection in rats exposed to the highest dose. Glyph did not decrease monoamines, tyrosine hydroxylase (TH), or mesencephalic TH+ cells when measured 2 or 16 days after the last Glyph injection. In contrast, Glyph decreased specific binding to D1 dopamine (DA) receptors in the nucleus accumbens (NAcc) when measured 2 days after the last Glyph injection. Microdialysis experiments showed that a systemic injection of 150 mg Glyph/kg BW decreased basal extracellular DA levels and high-potassium-induced DA release in striatum. Glyph did not affect the extracellular concentrations of 3,4-dihydroxyphenylacetic acid or homovanillic acid. These results indicate that repeated Glyph exposure results in hypoactivity accompanied by decreases in specific binding to D1-DA receptors in the NAcc, and that acute exposure to Glyph has evident effects on striatal DA levels. Additional experiments are necessary in order to unveil the specific targets of Glyph on dopaminergic system, and whether Glyph could be affecting other neurotransmitter systems involved in motor control.

Atrazine is primarily responsible for the toxicity of long-term exposure to a combination of atrazine and inorganic arsenic in the nigrostriatal system of the albino rat.

Chronic and simultaneous exposure to a variety of chemicals present in the environment is an unavoidable fact. However, given the complexity of studying chemical mixtures, most toxicological studies have focused on the effects of short-term exposure to single substances. The aim of this study was to evaluate the effects on the nigrostriatal system of the chronic, simultaneous exposure to two widely distributed substances that have been identified as potential dopaminergic system toxicants, inorganic arsenic (iAs) and atrazine (ATR). Six groups of rats were treated daily for one year with atrazine (10mg ATR/kg), inorganic arsenic (0.5 or 50mgiAs/L of drinking water), or a combination of ATR+0.5mgiAs/L or ATR+50mgiAs/L. The 50mgiAs/L group showed locomotor hypoactivity, while all treatments decreased motor coordination in contrast no effects of treatment were found on the place and response learning tasks. Regarding markers for liver and muscle damage, there were no differences between groups in creatine kinase (CK) or aspartate transaminase (AST) activities, while decreases in lactate dehydrogenase (LDH) levels were found in some exposed groups. The striatal DA content was significantly reduced in ATR, 0.5mgiAs/L, ATR+0.5mgiAs/L, and ATR+50mgiAs/L groups, in comparison to the control group. The number of mesencephalic tyrosine hydroxylase positive cells decreased in the ATR and ATR+0.5mgiAs/L groups compared to the control. In contrast, immunoreactivity to cytochrome oxidase was reduced compared to the control in all treated groups, except for the group treated with 0.5iAsmg alone. Our results indicate that ATR has deleterious effects on dopaminergic neurons and that the combination of ATR and iAs does not exacerbate these effects.

Repeated exposure to the herbicide atrazine alters locomotor activity and the nigrostriatal dopaminergic system of the albino rat.

Atrazine (ATR) is used as a pre- and post-emergent herbicide; although banned in several countries of the European Community, it is still used extensively around the world. A recent study in rats has shown that chronic, daily exposure to 10 mg ATR/kg BW causes hyperactivity, disrupts motor coordination and learning of behavioral tasks, and decreases dopamine levels in the brain. In order to evaluate the short-term effect of ATR exposure on locomotor activity, monoamine markers, and antioxidants, adult male Sprague-Dawley rats received six IP injections of 100 mg ATR/kg BW or vehicle over two weeks. After every ATR injection we found hypoactivity that lasted up to five days, and it was accompanied by reductions in levels of striatal DA, DOPAC, and HVA without any alteration in the striatal expression of the mRNAs for Mn-SOD, Trx-1, DAR-D(1), or DAR-D(2). In contrast, in the nucleus accumbens no changes in monoamine markers were observed, and a down-regulation of Trx-1 expression was detected shortly after the ATR treatment. Moreover, in the ventral midbrain, we found that ATR induced a down-regulation of mRNA for Th and DAT, but it increased VMAT2 mRNA expression. Decreases of monoamine levels and of locomotor activity disappeared three months after ATR treatment; however, an amphetamine challenge (1 mg/kg) given two months after the ATR treatment resulted in a significant stimulation in the exposed group, revealing hidden effects of ATR on dopaminergic systems. These results indicate that ATR exposure differentially modifies the dopaminergic systems, and these modifications may underlie the behavioral changes observed.

Evaluation of plasmid permanence in transfected cells after transplantation into the rat brain.

Plasmid retention after long-term transplantation has been one of the major technical limitations for transplantation studies. This study describes the use of a modified protocol of Hirt and a SYBR Green-based quantitative real-time PCR (qPCR) to recover and quantify a vector containing a specific transgene in transfected cells after brain transplantation. We compared various methods for sample processing and recovery of extrachromosomal DNA suitable for qPCR. The modified protocol of Hirt was the most reliable for optimal plasmid recovery from transplanted tissue with minimal loss of plasmid DNA compared to a commercial kit or TRIzol(®) protocols. The PCR protocol for plasmid and transgene detection included the design of two highly specific primer sets to detect the sequence for the human glutamate decarboxylase 1 (hGAD(67)) transgene by SYBR Green-based qPCR, and to confirm the presence of vector pREP10 hGAD(67) by end-point PCR. We used a standard curve constructed from serial dilutions of pure plasmid pREP10 hGAD(67) as reference in qPCR experiments to determine the number of plasmid copies recovered from cultured cells and tissue samples after Hirt extraction. Then, plasmid permanence was evaluated in transplanted tissues after different time intervals, and plasmid loss in the tissue of interest was found to be time dependent. In this study we describe an easy, highly specific, low-cost, and reliable method for plasmid recovery and quantification of a transgene of interest in long-term brain transplantation studies; use of this method may be extended to other transplantation models.

Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel.

Chemotropic proteins guide neuronal projections to their final target during embryo development and are useful to guide axons of neurons used in transplantation therapies. Site-specific delivery of the proteins however is needed for their application in the brain to avoid degradation and pleiotropic affects. In the present study we report the use of Poly (ethylene glycol)-Silica (PEG-Si) nanocomposite gel with thixotropic properties that make it injectable and suitable for delivery of the chemotropic protein semaphorin 3A. PEG-Si gel forms a functional gradient of semaphorin that enhances axon outgrowth of dopaminergic neurons from rat embryos or differentiated from stem cells in culture. It is not cytotoxic and its properties allowed its injection into the striatum without inflammatory response in the short term. Long term implantation however led to an increase in macrophages and glial cells. The inflammatory response could have resulted from non-degraded silica particles, as observed in biodegradation assays.

Chronic atrazine exposure causes disruption of the spontaneous locomotor activity and alters the striatal dopaminergic system of the male Sprague-Dawley rat.

The herbicide atrazine (ATR) is widely used around the world, and is a potential toxicant of the dopaminergic systems. Nigrostriatal and mesolimbic systems are the two major dopaminergic pathways of the central nervous system; they play key roles mediating a wide array of critical motor and cognitive functions. We evaluated the effects of exposing male rats for one year to 10 mg ATR/kg B.W. on these systems using motor and cognitive tasks and measuring monoamine content in the striatum, nucleus accumbens, prefrontal cortex, and hypothalamus. ATR administration resulted in impaired motor coordination and greater spontaneous locomotor activity only after 10 to 12 months of exposure. Chronic exposure to 10 mg ATR decreased striatal dopamine, but had no effect on accumbal, hypothalamic or cortical monoamine content. Chronic ATR exposure caused discrete changes in learning tasks that involve either the striatum or the nucleus accumbens. These results indicate that chronic exposure to ATR preferentially targets the nigrostriatal dopaminergic pathway, in comparison to the other dopaminergic pathways evaluated in this study, inducing behavioral and neurochemical alterations. In order to unveil the full extent of atrazine's effects on the nervous system, other neurochemical systems should be considered in future studies.

Strategies for the development of cell lines for ex vivo gene therapy in the central nervous system.

Disorders of the central nervous system (CNS) as a result of trauma or ischemic or neurodegenerative processes still pose a challenge for modern medicine. Due to the complexity of the CNS, and in spite of the advances in the knowledge of its anatomy, pharmacology, and molecular and cellular biology, treatments for these diseases are still limited. The development of cell lines as a source for transplantation into the damaged CNS (cell therapy), and more recently their genetic modification to favor the expression and delivery of molecules with therapeutic potential (ex vivo gene therapy), are some of the techniques used in search of novel restorative strategies. This article reviews the different approaches that have been used and perfected during the last decade to generate cell lines and their use in experimental models of neuronal damage, and evaluates the prospects of applying these methods to treat CNS disorders.

Chronic exposure to low levels of inorganic arsenic causes alterations in locomotor activity and in the expression of dopaminergic and antioxidant systems in the albino rat.

Several studies have associated chronic arsenicism with decreases in IQ and sensory and motor alterations in humans. Likewise, studies of rodents exposed to inorganic arsenic ((i)As) have found changes in locomotor activity, brain neurochemistry, behavioral tasks, oxidative stress, and in sensory and motor nerves. In the current study, male Sprague-Dawley rats were exposed to environmentally relevant doses of (i)As (0.05, 0.5 mg (i)As/L) and to a high dose (50 mg (i)As/L) in drinking water for one year. Hypoactivity and increases in the striatal dopamine content were found in the group treated with 50 mg (i)As/L. Exposure to 0.5 and 50 mg (i)As/L increased the total brain content of As. Furthermore, (i)As exposure produced a dose-dependent up-regulation of mRNA for Mn-SOD and Trx-1 and a down-regulation of DAR-D2 mRNA levels in the nucleus accumbens. DAR-D1 and Nrf2 mRNA expression were down-regulated in nucleus accumbens in the group exposed to 50 mg (i)As/L. Trx-1 mRNA levels were up-regulated in the cortex in an (i)As dose-dependent manner, while DAR-D1 mRNA expression was increased in striatum in the 0.5 mg (i)As/L group. These results show that chronic exposure to low levels of arsenic causes subtle but region-specific changes in the nervous system, especially in antioxidant systems and dopaminergic elements. These changes became behaviorally evident only in the group exposed to 50 mg (i)As/L.

Lack of effect of intranigral transplants of a GABAergic cell line on absence seizures.

The substantia nigra pars reticulata (SNpr) is involved in controlling a variety of seizure phenomena. Intranigral transplants of GABAergic cells have been shown to decrease the severity of already established epileptic seizures, but the effects observed have been short-lived. This study evaluated the ability of intranigral transplants of GABA-producing cells to reduce spontaneous absence seizures in a genetic animal model for periods up to 3 months after transplantation. Intranigral transplants did not induce any behavioral deficits in the animals, and they did not form tumors; however, the transplants failed to decrease absence seizures in the genetic model. The assumed increase in intranigral levels of GABA after the transplants may be insufficient to counteract all the factors involved in generating the absence seizures; in this animal model, it may be necessary to further decrease nigral activity by implanting GABAergic cells in another area. These results bear down on the fact that cell transplants need to be tailored for each type of convulsive disorder in terms of the type of cells delivered and the location of the transplants.

Glutamatergic excitation and GABA release from a transplantable cell line.

The cell line M213-2O CL-4 was derived from cell line M213-2O and further modified to express human glutamate decarboxylase (hGAD-67), the enzyme that synthesizes GABA. Brain transplants of this cell line in animal models of epilepsy have been shown to modulate seizures. However, the mechanisms that underlie such actions are unknown. The purpose of the present study was to characterize this cell line and its responsiveness to several depolarizing conditions, in order to better understand how these cells exert their effects. Intracellular GABA levels were 34-fold higher and GAD activity was 16-fold higher in clone M213-2O CL-4 than in M213-2O. Both cell lines could take up [³H]GABA in vitro, and this uptake was prevented by nipecotic acid. By combining GABA release measurements and calcium imaging in vitro, we found that high extracellular K(+), zero Mg(2+), or glutamate activated M213-2O CL-4 cells and resulted in GABA release. The response to glutamate appeared to be mediated by AMPA/NMDA-like receptors. High KCl-induced GABA release was prevented when a Ca(2+)-free Krebs solution was used, suggesting an exocytotic-like mechanism. These results indicate that the cell line M213-2O CL-4 synthesizes, releases, and takes up GABA in vitro, and can be activated by depolarizing stimuli.

Beta-amyloid protein (25-35) disrupts hippocampal network activity: role of Fyn-kinase.

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.