tetrodotoxin and Memory-Disorders

Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region. We investigated whether mTBI induces morphological and pathophysiological alterations in the CA1 using the controlled cortical impact (CCI) model. Seven days after CCI, animals subjected to mTBI showed cognitive impairment in the passive avoidance test and deficits to long-term potentiation (LTP) of synaptic transmission. Deficiencies in inducing or maintaining LTP were likely due to an observed reduction in the activation of NMDA but not AMPA receptors. Significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs) were also observed 7 days after CCI. Design-based stereology revealed that although the total number of neurons was unaltered, the number of GABAergic interneurons is significantly reduced in the CA1 region 7 days after CCI. Additionally, the surface expression of α1, ß2/3, and γ2 subunits of the GABAA receptor were reduced, contributing to a reduced mIPSC frequency and amplitude, respectively. Together, these results suggest that mTBI causes a significant reduction in GABAergic inhibitory transmission and deficits to NMDA receptor mediated currents in the CA1, which may contribute to changes in hippocampal excitability and subsequent cognitive impairments after mTBI.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Avoidance Learning; Brain Injuries; CA1 Region, Hippocampal; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; GABAergic Neurons; Glucose Transporter Type 1; Glutamate Decarboxylase; Inhibitory Postsynaptic Potentials; Interneurons; Male; Memory Disorders; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, GABA-A; Sodium Channel Blockers; Tetrodotoxin; Time Factors

Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Aβ-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K(+) currents. In addition, NTR1 reversed Aβ1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Aβ-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Aβ neurotoxicity.

Topics: Amyloid; Amyloid beta-Peptides; Animals; Disease Models, Animal; Ginsenosides; Hippocampus; Long-Term Potentiation; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Neurons; Potassium; Tetrodotoxin

Long-term memory requires fine-tuning regulation of gene expression in specific neural circuits of the brain. Transcriptional regulation of gene programs is a key mechanism for memory storage and its deregulation may contribute to synaptic and cognitive dysfunction in memory disorders. The molecular mechanisms underlying changes on activity-dependent gene expression in Alzheimer's disease (AD) are largely unknown.. We analyzed the expression of activity-dependent genes regulated by the cAMP response element binding protein (CREB) and activation of CREB and its coactivator CREB-regulated transcription coactivator 1 (CRTC1) in control and mutant β-amyloid precursor protein (APP(Sw,Ind); Swedish and Indiana mutations) transgenic mice.. Gene expression analyses revealed specific downregulation of a subset of well-known activity-induced CREB-dependent genes, including c-fos, Bdnf and Nr4a2, in the hippocampus of memory-impaired APP(Sw,Ind) transgenic mice. Activity-dependent CREB transcription induced by calcium/cAMP signals is disrupted through a mechanism involving deregulation of calcium/calcineurin-mediated dephosphorylation and activation of CRTC1. Expression of CRTC1 and pharmacological activation of L-type voltage-gated calcium channels reverse the deficits in CRTC1-mediated transcription in APP(Sw,Ind) neurons.. Our results suggest that CRTC1 dysfunction caused by Aβ accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Calcineurin; Calcium; Cells, Cultured; Cerebral Cortex; Cyclic AMP; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Neurons; Peptide Fragments; Tetrodotoxin; Transcription Factors; Transfection

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.

Topics: Animals; Arabidopsis Proteins; CA1 Region, Hippocampal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cells, Cultured; Conditioning, Psychological; Electric Stimulation; Excitatory Postsynaptic Potentials; Fear; GABA Antagonists; Green Fluorescent Proteins; Histone Deacetylases; Humans; In Vitro Techniques; Intramolecular Transferases; Learning Disabilities; Long-Term Potentiation; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Neurons; Patch-Clamp Techniques; Picrotoxin; Rotarod Performance Test; Sodium Channel Blockers; Synapses; Tetrodotoxin; Transfection

This study was aimed at comparing the effect of unilateral hippocampal inactivation with tetrodotoxin (TTX) and lidocaine on spatial memory consolidation. Both drugs block voltage-dependent sodium channels. However, TTX and lidocaine differ in the duration of their effects, with maximum TTX effect between 30 min and 120 min, washing out in 24 hours. Lidocaine maximum effect occurs 20-30 minutes after administration. Our experimental subjects, twenty-four 3-month-old Wistar rats, were unilaterally implanted with stainless-steel cannulae aimed at the right dorsal hippocampus. Animals received four daily trials for 5 consecutive days. Control injections of 1 microl saline, or inactivating injections of 5 ng of TTX in 1 microl saline or lidocaine (2%) in 1 microl were made through a guide cannula 1 minute after the last trial from day 1 to day 4. Results showed that the groups that received TTX or lidocaine did not differ but were impaired regarding controls, suggesting that short-term consolidation processes can account for the memory impairment observed here.

Topics: Animals; Lidocaine; Male; Memory; Memory Disorders; Rats; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin

The aim of our study was to examine the supramammillary (SuM) area involvement in spatial memory. Sprague-Dawley rats with chronically implanted cannula in the supramammillary area were trained in two spatial memory tasks with different memory demands: reference and working memory. In the spatial reference memory task, the rats received microinjections in the SuM area of tetrodotoxin (TTX) (0.5 ng diluted in 0.5 microL of saline) or saline (0.5 microL). The microinjections were administered 30 min before the spatial training (day 4) (to assess the effect on acquisition) and on the following two days (days 5 and 6) the training was conducted without microinjections (to study the effect on consolidation). On the last training day (day 7), in order to assess the retrieval of spatial information, the rats received the microinjections 30 min before the spatial training. The spatial working memory used was a delayed-matching-to-position (DMTP) task. Spatial training was performed for seven days. During the first three days of the spatial training, the rats achieved a good spatial knowledge and learnt the working memory rule necessary to solve the spatial task. On days 4 and 6, the rats received microinjections to study involvement of the SuM area in working memory. The results showed that temporary inactivation of SuM area impairs both the rat's ability to solve a spatial working memory task with DMTP demands and the recovery of spatial information in a spatial reference memory task. We suggest that SuM area is involved in the rearrangement of spatial information during spatial working memory tasks with DMTP memory demands.

Topics: Anesthetics, Local; Animals; Behavior, Animal; Exploratory Behavior; Male; Mammillary Bodies; Maze Learning; Memory Disorders; Memory, Short-Term; Mental Recall; Microinjections; Rats; Rats, Sprague-Dawley; Space Perception; Tetrodotoxin; Time Factors

Understanding hippocampal participation in memory processes is one of the goals in neuroscience research. By blocking the hippocampus unilaterally in Wistar rats, we assessed the contribution of this brain structure to memory in a passive avoidance task. Subjects were distributed into four groups. Group 1 received tetrodotoxin (TTX) in the right hippocampus during acquisition and retrieval phases. Group 2 had the same procedure as group 1, except that the contralateral hippocampus was blocked during retrieval. Subjects from group 3 acquired the task with saline (both hippocampi intact) and retrieved with the right hippocampus inactivated. Finally, group 4 received TTX unilaterally 2 min after acquisition to determine the hippocampal role in consolidation. Results showed that group 2 was impaired, compared with the other groups, during retrieval. These findings reveal that the hippocampal contribution to this task differs from that in other tasks considered to be hippocampus dependent.

Topics: Animals; Avoidance Learning; Denervation; Functional Laterality; Hippocampus; Male; Memory Disorders; Neural Pathways; Neurons; Neuropsychological Tests; Rats; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin

The hippocampus is critical for navigation in an open field. One component of this navigation requires the subject to recognize the target place using distal cues. The experiments presented in this report tested whether blocking hippocampal function would impair open field place recognition. Hungry rats were trained to press a lever on a feeder for food. In Experiment 1, they were passively transported with the feeder along a circular trajectory. Lever pressing was reinforced only if the feeder was passing through a 60 degrees -wide sector. Thus, rats preferentially lever pressed in the vicinity of the reward sector indicating that they recognized its location. Tetrodotoxin (TTX) infusions aimed at the dorsal hippocampi caused rats to substantially increase lever pressing with no preference for any region. The aim of Experiment 2 was to determine whether the TTX injections caused a loss of place recognition or a general increase of lever pressing. A separate group of rats was conditioned in a stationary apparatus to press the lever in response to a light. The TTX injections did not abolish preferential lever pressing in response to light. Lever pressing increased less than half as much as the TTX-induced increase in Experiment 1. When these animals with functional hippocampi could not determine the rewarded period because the light was always off, lever pressing increased much more and was similar to the TTX-induced increase in Experiment 1. We conclude that the TTX inactivation of the hippocampi impaired the ability to recognize the reward place.

Topics: Anesthetics, Local; Animals; Behavior, Animal; Disease Models, Animal; Feeding Behavior; Hippocampus; Male; Memory; Memory Disorders; Orientation; Rats; Rats, Long-Evans; Space Perception; Tetrodotoxin

Injecting tetrodotoxin (TTX) into one hippocampus impaired avoidance of a place defined by distal cues while rats were on a slowly rotating arena. The impairment could be explained by a deficit in memory, navigation, or behavioral inhibition. Here, we show that the TTX injection abolished the ability of rats to organize place-avoidance behavior specifically when distal room and local arena cues were continuously dissociated. The results provide evidence that injecting TTX into one hippocampus specifically impaired the coordination of representations that support organized behavior because of the following: (1) rats normally coordinate separate room and arena avoidance memories; (2) the TTX injection spared spatial, relational, and representational memory, navigation, and behavioral inhibition; and (3) the TTX-induced impairment of place avoidance depended on the need to coordinate representations of local and distal stimuli.

Topics: Anesthetics, Local; Animals; Avoidance Learning; Behavior, Animal; Cognition; Hippocampus; Inhibition, Psychological; Male; Maze Learning; Memory; Memory Disorders; Rats; Rats, Long-Evans; Space Perception; Tetrodotoxin; Time Factors

Hippocampal activity is thought to encode spatial representations in a distributed associative network. This idea predicts that partial hippocampal lesions would spare acquisition and impair retrieval of a place response as long as enough connections remained intact to encode associations. Water maze experiments supported the predictions, but the prediction of impaired retrieval was not supported when tetrodotoxin (TTX) was injected into one hippocampus and rats were tested in a place avoidance task on a rotating arena with shallow water. The rotation dissociated relevant distal stimuli from irrelevant self-motion stimuli. To explain the discrepancy, we hypothesized that the segregation of relevant and irrelevant stimuli and stimuli association into representations are distinct hippocampus-dependent operations, and whereas associative representation is more sensitive to disruption during retrieval than learning, stimulus segregation is more sensitive to disruption during learning than during retrieval. The following predictions were tested: (1) the TTX injection would spare learning but (2) impair retrieval of a place response in the water maze, which has a high associative representational demand but a low demand for segregation; (3) the injection would impair learning but (4) spare retrieval of place avoidance in the rotating arena filled with water, which has a high demand for stimulus segregation but a low associative representational demand. All four predictions were confirmed. The hypothesis also explains the pattern of sparing and impairment after the TTX injection in other place avoidance task variants, leading us to conclude that stimulus separation and association representation are dissociable functions of the hippocampus.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Avoidance Learning; Behavior, Animal; Escape Reaction; Hippocampus; Male; Maze Learning; Memory Disorders; Mental Recall; Rats; Rats, Long-Evans; Space Perception; Tetrodotoxin; Time Factors

In this study, tetrodotoxin (TTX) inactivation was employed to evaluate the involvement of the rat's orbitofrontal cortex (OFC) in hippocampus-dependent spatial memory using Morris water maze (MWM) and place avoidance learning (PAL) tasks. In Experiment 1, rats trained in MWM task with two blocks of four trials per day for 3 consecutive days received bilateral injections of either TTX or saline into the OFC 60 min before each daily training session. The acquisition of spatial memory was evaluated 24h after the last training day and it was shown an impairment by the TTX. In Experiment 2, bilateral intra-OFC injections of TTX or saline were made immediately after two blocks of four trials. Testing 24h later, it was revealed that TTX also impairs spatial memory consolidation. In Experiments 3 and 4, rats were trained in a single 30-min session to avoid a 60 degrees segment of the stable circular (80-cm diameter) arena, entering which was punished by a mild shock (PAL task) and retention was tested 24h later in a 30-min extinction session. Bilateral injections of TTX or saline were made into the OFC 60 min before training or immediately after training. Again, TTX impaired the place avoidance retention when it was injected into the OFC either before (acquisition phase) or after (consolidation phase) training. These findings indicate that functional integrity of the OFC is necessary for both the acquisition and the consolidation of hippocampus-dependent spatial memory in rats.

Topics: Anesthetics, Local; Animals; Avoidance Learning; Discrimination Learning; Frontal Lobe; Hippocampus; Hydrazones; Male; Memory; Memory Disorders; Neural Pathways; Phenols; Rats; Rats, Long-Evans; Space Perception; Tetrodotoxin

Rats were trained on an inhibitory avoidance task to study the effects of post-training administration of tetrodotoxin (TTX, which temporarily inactivates neural activity) on memory consolidation. During training, independent groups of rats received either a mild foot shock (0.8 mA) or a stronger (1.0 mA) foot shock. TTX was administered bilaterally into the dorsal hippocampus immediately after training, and memory of the task was measured 48 h later. We corroborated the typical amnesic effect of intrahippocampal infusions of TTX in those rats trained with the mild-intensity foot shock. More importantly, with the stronger foot shock, the same treatment was ineffective in producing amnesia. These results suggest that, after an enhanced learning experience, other brain regions are also activated, which may compensate for the amnesic effect of TTX infusions into the hippocampus.

Topics: Animals; Avoidance Learning; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Memory; Memory Disorders; Neural Inhibition; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reaction Time; Tetrodotoxin