Plasticity In Hippocampal Neurons Research Articles

Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model.

Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by combination of the intravenous photosensitive dye Rose Bengal administration with focused high-intensity illumination of the frontal bone, was shown to provoke a pronounced deficit in step-through passive avoidance performance in rats without concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS-111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1 h after ischaemic lesion and then for 9 post-operative days, with the last administration 15 min before testing, attenuated the deficit. This treatment significantly diminished the volume of the infarcted area. Thus, post-ischaemic injection of GVS-111 demonstrated both cognition-restoring and neuroprotective properties. The cognition-restoring effect is probably based on an increase in neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS-111 combine antioxidant activity with the ability to attenuate glutamate-provoked neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates the main metabolic shifts involved in pathogenesis of brain ischaemia.

Self-stimulation rewarding experience induced alterations in dendritic spine density in CA3 hippocampal and layer V motor cortical pyramidal neurons

Self-stimulation rewarding experience induced alterations in the numerical density of spines in CA3 hippocampal and layer V motor cortical pyramidal neurons in adult male Wistar rats was evaluated. Self-stimulation experience was provided 1 h daily over a period of 10 days through stereotaxically implanted bipolar stainless steel electrodes bilaterally in lateral hypothalamus and substantia nigra-ventral tegmental area. After 10 days, rats were killed and the hippocampus and motor cortex were processed for rapid Golgi staining procedure. The dendritic spine densities were studied in CA3 hippocampal and layer V motor cortical pyramidal neurons. The spine densities were quantified in five successive segments of 15.2 μm up to a distance of 76 μm. Apical dendrites were classified as mainshaft, sub branch, oblique shaft-I, oblique shaft-II, primary branch; and basal dendrites as main shaft, primary branch and secondary branch. A grand total of 864 CA3 hippocampal and 1 008 layer V motor cortical dendrites were analysed for spine counting in different groups of rats. The results revealed a significant ( P<0.001; ANOVA, F-test) increase in the number of spines in all the categories of dendrites in apical and basal regions in both hippocampal and motor cortical neurons in self-stimulation group of rats. Such changes were not observed either in sham control, experimenter-administered or normal control groups of rats. The self-stimulation induced increase in the spine density suggests an increase in the postsynaptic receptive field in CA3 hippocampal and layer V motor cortical neurons. This might enhance the efficacy of synaptic transmission in these neurons. Our study clearly demonstrated the self-stimulation rewarding experience induced postsynaptic plasticity in hippocampal and motor cortical pyramidal neurons.

The influence of (±)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices

Little is known about the mechanisms of action of kava pyrones which are the pharmacological active compounds of the plant Piper methysticum Forst. We investigated the effects of the synthetic kava pyrone (±)-kavain on long-term potentiation (LTP) in the CA1-region of guinea pig hippocampal slices. (±)-Kavain reduced the amplitudes of extracellular field potential changes evoked by electrical stimulation in a concentration dependent manner. These effects were reversible. In experiments with LTP no changes were found in the presence of (±)-kavain. In conclusion, our findings suggest (±)-kavain to be an effective drug in modulating excitatory signals in the hippocampus of guinea pigs. Additionally, no alterations on synaptic plasticity in hippocampal neurons for this kava pyrone can be presumed.

Analysis of the tetanic and post-tetanic components of intradendritic Ca 2+ signals in hippocampal CA1 neurons

The importance of both the activation of second messenger cascades and an increase of the intracellular Ca 2+ concentration for the induction of synaptic plasticity in hippocampal CA1 neurons is well established. Using the dye Calcium Green-1, we analysed the Ca 2+ increases evoked by different 100-Hz tetanization paradigms commonly used to induce long-term potentiation. We found that the normalized total area of fluorescence intensity changes ( F/ F 0) was correlated with both the strength and the duration of tetanization. Furthermore, the normalized area of fluorescence intensity changes during the time of tetanization (tetanic component) correlated strongly in a linear manner with the tetanization duration. Moreover, the tetanic component strongly determined the area of the post-tetanic Ca 2+ signal. Interestingly, the normalized relationship of the post-tetanic Ca 2+ signal to the total Ca 2+ change decreased with prolonged tetanizations. In contrast, with an increased stimulation strength, a positive correlation of the relationship of the post-tetanic component to the total amount Ca 2+ could be obtained. The time constants of the Ca 2+ extrusion depend linearly on both the tetanization duration and the amount of the tetanic Ca 2+ signal. Our data demonstrate that augmenting the stimulation strength leads to a respective increase of the post-tetanic Ca 2+ portion within the total Ca 2+ signal, whereas a prolongation of the tetanization duration does not. Thus, no further significant prolongation of the Ca 2+ signal occurs during increased durations of tetanization.

Prolonged Sodium Channel Inactivation Contributes to Dendritic Action Potential Attenuation in Hippocampal Pyramidal Neurons

During low-frequency firing, action potentials actively invade the dendrites of CA1 pyramidal neurons. At higher firing rates, however, activity-dependent processes result in the attenuation of back-propagating action potentials, and propagation failures occur at some dendritic branch points. We tested two major hypotheses related to this activity-dependent attenuation of back-propagating action potentials: (1) that it is mediated by a prolonged form of sodium channel inactivation and (2) that it is mediated by a persistent dendritic shunt activated by back-propagating action potentials. We found no evidence for a persistent shunt, but we did find that cumulative, prolonged inactivation of sodium channels develops during repetitive action potential firing. This inactivation is significant after a single action potential and continues to develop during several action potentials thereafter, until a steady-state sodium current is established. Recovery from this form of inactivation is much slower than its induction, but recovery can be accelerated by hyperpolarization. The similarity of these properties to the time and voltage dependence of attenuation and recovery of dendritic action potentials suggests that dendritic sodium channel inactivation contributes to the activity dependence of action potential back-propagation in CA1 neurons. Hence, the biophysical properties of dendritic sodium channels will be important determinants of action potential-mediated effects on synaptic integration and plasticity in hippocampal neurons.

Redox modulation of synaptic responses and plasticity in rat CA1 hippocampal neurons.

Effects of redox reagents on excitatory and inhibitory synaptic responses as well as on the bidrectional plasticity of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses were studied in CA1 pyramidal neurons in rat hippocampal slices. The oxidizing agent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB, 200 microM) did not affect AMPA, GABAA or GABAB receptor-mediated synaptic responses or the activation of presynaptic metabotropic receptors. However, DTNB irreversibly decreased (by approximately 50%) currents evoked by focal application of NMDA. DTNB also decreased the NMDA component of the EPSC. The reversal potential of NMDA currents and the Mg2+ block were not modified. In the presence of physiological concentrations of Mg2+ (1.3 mM), DTNB did not affect the NMDA receptor-dependent induction of long-term potentiation (LTP) or long-term depression (LTD) expressed by AMPA receptors. In contrast, DTNB fully prevented LTP and LTD induced and expressed by NMDA receptors. Plasticity of NMDA receptor-mediated synaptic responses could be reinstated by the reducing agent tris-(2-carboxyethyl) phosphine (TCEP, 200 microM). These results suggest that persistent, bidirectional changes in synaptic currents mediated by NMDA receptors cannot be evoked when these receptors are in an oxidized state, whereas NMDA-dependent LTP and LTD are still expressed by AMPA receptors. Our observations raise the possibility of developing therapeutic agents that would prevent persistent excitotoxic enhancement of NMDA receptor-mediated events without blocking longterm modifications of AMPA receptor-mediated synaptic responses, thought to underlie memory processes.

A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.

The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.

Associative synaptic plasticity in hippocampal CA1 neurons is not sensitive to unpaired presynaptic activity.

1. Hebbian or associative synaptic plasticity has been proposed to play an important role in learning and memory. Whereas many behaviorally relevant stimuli are time-varying, most experimental and theoretical work on synaptic plasticity has focused on stimuli or induction protocols without temporal structure. Recent theoretical studies have suggested that associative plasticity sensitive to only the conjunction of pre- and postsynaptic activity is not an effective learning rule for networks required to learn time-varying stimuli. Our goal in the current experiment was to determine whether associative long-term potentiation (LTP) is sensitive to temporal structure. We examined whether the presentation of unpaired presynaptic pulses in addition to paired pre- and postsynaptic activity altered the induction of associative LTP. 2. By using intracellular recordings from CA1 pyramidal cells, associative long-term potentiation (LTP) was induced in a control pathway by pairing a single presynaptic pulse with postsynaptic depolarization every 5 s (50-70 x). The experimental pathway received the same training, with additional unpaired presynaptic pulses delivered in close temporal proximity, either after or before associative pairing. Five separate sets of experiments were performed with intervals of -200, -50, +50, +200, or +800 ms. Negative intervals indicate that the unpaired presynaptic pulse was presented before the depolarizing pulse. Our results showed that the presence of unpaired presynaptic pulses, occurring either before or after pairing, did not significantly alter the magnitude of LTP. 3. The experimental design permitted an analysis of whether changes in paired-pulse facilitation (PPF) occur as a result of associative LTP. The average degree of PPF was the same before and after LTP. However, there was a significant inverse correlation between the initial degree of PPF and the degree of PPF after LTP. There was no relationship between the change in PPF, and whether the first or second pulse had been paired with depolarization. 4. These results indicate that the presence of unpaired presynaptic pulses does not alter the induction of synaptic plasticity, suggesting that plasticity of the Schaffer collateral-CA1 synapse is primarily conjunctive rather than correlative.

Neonatal Isolation Enhances Hippocampal Dentate Response to Tetanization in Freely Moving Juvenile Male Rats

The impact of early neonatal isolation on measures of hippocampal neuronal plasticity was examined in freely moving male rats at 30 days of age. Beginning on Postnatal (PN) Day 2, one-half of pups from each experimental litter were individually isolated from the nest, dam, and siblings for a period of 1 h per day over PN Days 2-9, while their siblings remained in the nest. In addition, randomly selected litters served as unhandled controls. On PN Day 26 all pups were weaned and chronically implanted for recording of evoked field potentials and induction of hippocampal long-term potentiation. At 30 days of age, pups from the three treatment groups (isolated, nonisolated siblings, and unhandled controls) were tested for their ability to establish and maintain long-term potentiation across the perforant path/hippocampal dentate granule cell synapse. Changes in population EPSP slope and population spike amplitude (PSA) recorded following tetanization were used to assess the effects of neonatal isolation on hippocampal response measures. No significant between-group differences were obtained for input/output response curves constructed prior to tetanization. All three groups showed immediate and significant enhancement of the PSA measure at 15 min posttetanization. The level of PSA enhancement obtained from previously isolated pups was significantly greater than that obtained from both the nonisolated sibling and unhandled control groups. PSA enhancement in both the nonisolated and unhandled animals decayed to baseline 48-72 h after tetanization, while isolates showed no significant decay of the PSA measure at this period. Neonatal isolation was found to significantly enhance both the magnitude and duration of dentate granule cell response to tetanizing stimulations applied during early adolescence, a full 3 weeks after termination of the isolation paradigm. The results suggest that regularly repeated isolation stress occurring during infancy has an enduring impact on dentate neuroplasticity.

Loss of 5-HT 1A receptor mRNA in the dentate gyrus of the long-term adrenalectomized rats and rapid reversal by dexamethasone

Two months after bilateral adrenalectomy, 5-HT 1A receptor mRNA labelling was decreased in the granular cell layer of the dentate gyrus but not in the pyramidal cell layer of Ammon's horn. Two month adrenalectomized rats given dexamethasone (10 υg/ml saline) 24 or 72 h before perfusion showed a progressive recovery in 5-HT 1A mRNA labelling in the dentate gyrus. 5-HT 1A expression may underlie hippocampal neuronal plasticity after long-term adrenalectomy.

Adrenal steroids and plasticity of hippocampal neurons: toward an understanding of underlying cellular and molecular mechanisms.

The hippocampal formation of the mammalian brain and its homologue in birds are involved in spatial information processing as well as in aspects of learning and memory (Sherry et al., 1989; Krebs et al., 1989; Eichenbaum and Otto, 1992), and the size of the hippocampus is sometimes an index of the degree to which an animal is involved in such behavior. For example, the volume of the hippocampal complex relative to brain and body size is significantly greater in bird species that store food than in species that do not (Krebs et al., 1989). Furthermore, in two species of kangaroo rat, differences in foraging behavior in terms of use of environmental space positively correlate with hippocampal size (Jacobs and Spencer, 1991), and in mice, hippocampal size correlates positively with maze performance (Crusio and Schwegler, 1991; Crusio et al., 1990). Thus the hippocampus varies in size according to the importance of spatial memory for the species, but it is not known thus far whether it is malleable in the course of an individual animal's life. The hippocampus is also a brain structure with many intriguing histological and neurochemical properties, including sensitivity to a variety of hormones

Heightened synaptic plasticity of hippocampal CA1 neurons during a cholinergically induced rhythmic state.

Brain cholinergic neurons are critical for memory function and their loss may contribute to memory impairment in Alzheimer's disease. One role of cholinergic neurons is to elicit an oscillatory activity called theta rhythm in the hippocampus, a brain region involved in memory processing. Theta rhythm occurs during periods of learning, but its effect on the synaptic plasticity that underlies learning remains unclear. We have studied synaptic plasticity in hippocampal slices during theta-frequency oscillations induced by a cholinergic agonist. Here we report that during these oscillations, synapses are in a state of heightened plasticity and can be modified by what would otherwise be ineffective stimulation. This heightened plasticity is sensitive to the timing of incoming stimuli with respect to the oscillatory activity. The results suggest that cholinergic systems may affect memory formation through the induction of an oscillatory state in which the requirements for synaptic plasticity are dramatically altered.

Systemic interleukin-1β decreases brain-derived neurotrophic factor messenger RNA expression in the rat hippocampal formation

Brain-derived neurotrophic factor is selectively expressed at relatively high levels in the rat hippocampal formation (for review, see Ref. 12; see also Refs 8, 13, 19, 20, 27) where it is thought to be involved in mechanisms of neurodegeneration and/or neural protection related to the plasticity of hippocampal neurons. Functional responses to brain-derived neurotrophic factor appear to be mediated by a tyrosine receptor kinase B with the possible involvement of the p75 low-affinity nerve growth factor receptor protein. Among the many characteristics of Alzheimer's disease is an upregulation of immune mediators in and around senile plaques in Alzheimer's disease. Recently, interleukin-1 has been shown to be detrimental to the long-term survival of embryonic hippocampal neurons in culture. Thus, if the same occurs in vivo, it is possible that the accumulation of interleukin-1 in Alzheimer's disease hippocampus may be responsible for altered hippocampal neuron synaptic plasticity. This may occur either by a direct action of interleukin-1 on hippocampal neurons or possibly indirectly by stimulating beta-amyloid production. Other indirect mechanisms may involve growth or survival factors such as the neurotrophin brain-derived neurotrophic factor which is thought to play an important role in the plastic responses of hippocampal neurons. A recent study showed that brain-derived neurotrophic factor mRNA is selectively decreased in the dentate gyrus in Alzheimer's disease. The reason(s) for the decrease of brain-derived neurotrophic factor mRNA is not known, but one possibility may be associated with the enhanced expression of interleukin-1 in the hippocampus of Alzheimer's disease patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of the Golgi/electron microscopy technique for cell identification in immunocytochemical, retrograde labeling, and developmental studies of hippocampal neurons.

In this study the Golgi/electron microscopy (EM) technique has been used for an analysis of the fine structure, specific synaptic connections, and differentiation of neurons in the hippocampus and fascia dentata of rodents. In a first series of experiments the specific synaptic contacts formed between cholinergic terminals and identified hippocampal neurons were studied. By means of a variant of the section Golgi impregnation procedure, Vibratome sections immunostained for choline acetyltransferase, the acetylcholine-synthesizing enzyme, were Golgi-impregnated in order to identify the target neurons of cholinergic terminals in the hippocampus. It could be shown with this combined approach that cholinergic septohippocampal fibers form a variety of synapses with different target structures of the Golgi-impregnated and gold-toned hippocampal neurons. In this report cholinergic synapses on the heads of small spines, the necks of large complex spines, dendritic shafts, and cell bodies of identified dentate granule cells are described. The variety of cholinergic synapses suggests that cholinergic transmission in the fascia dentata is a complex event. Next, the Golgi/EM technique was applied to Vibratome sections that contained retrogradely labeled neurons in the hilar region of the fascia dentata following horseradish peroxidase (HRP) injection into the contralateral hippocampus. With this combined approach some of the hilar cells projecting to the contralateral side were identified as mossy cells by the presence of retrogradely transported HRP in thin sections through these Golgi-impregnated and gold-toned neurons. Our findings suggest that the mossy cells are part of the commissural/associational system terminating in the inner molecular layer of the fascia dentata. They are mainly driven by hilar collaterals of granule cell axons that form giant synapses on their dendrites. Finally, the Golgi/EM procedure was used to study the differentiation and developmental plasticity of hippocampal and dentate neurons in transplants and slice cultures of hippocampus. Under both experimental conditions, the differentiating neurons are deprived of their normal laminated afferent innervation but develop their major cell-specific characteristics including a large number of postsynaptic structures (spines). As revealed in thin sections of gold-toned identified cells, all these spines formed synapses with presynaptic boutons suggesting sprouting of the transplanted and cultured neurons, respectively. Altogether, the present report demonstrates the usefulness of the Golgi/EM technique, particularly of the section impregnation procedure, for a variety of studies requiring the identification of individual neurons at the ultrastructural level.

Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases.

In the mammalian central nervous system, receptors for excitatory amino acid neurotransmitters such as the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-kainate receptor mediate a large fraction of excitatory transmission. Currents induced by activation of the AMPA-kainate receptor were potentiated by agents that specifically stimulate adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A (PKA) activity or were supported by intracellular application of the catalytic subunit of PKA by itself or in combination with cAMP. Furthermore, depression of these currents by a competitive inhibitor of PKA indicates that AMPA-kainate receptors are regulated by endogenous PKA. Endogenous protein phosphatases also regulate these receptors because an inhibitor of cellular phosphates enhanced kainate currents. Modulation of PKA and phosphatases may regulate the function of these receptors and thus contribute to synaptic plasticity in hippocampal neurons.

Electrolytic entorhinal lesions cause seizures

The entorhinal cortex is a key site of interneuronal communication between a variety of cortical and subcortical areas and hippocampal formation. Lesioning the entorhinal cortex is commonly used in studies of the hippocampal formation, animal behavior and neuronal plasticity. We have found that electrolytic destruction of the entorhinal cortex consistently produces limbic seizure activity in rats. The propensity of lesions in this area for producing seizure activity may facilitate insights into the normal function of this network of neural connections. This unexpected phenomenon represents a potential confounding variable for all researchers using this method for making brain lesions.

Identification of pyramidal cells as the critical elements in hippocampal neuronal plasticity during learning.

The activity of single neurons recorded from rabbit hippocampus during classical conditioning of the nictitating membrane reflex was studied. All cells were first categorized according to their responses after fornix stimulation--i.i., antidromic activation, orthodromic activation, or no activation. The majority of cells that were antidromically activated--pyramidal cells--showed a highly positive correlation between the pattern of unit discharge and the topography of the nicititating membrane response within trial periods. Units that were orthodromically driven by fornix stimulation tended to inhibit during the presentation of trial stimuli, whereas most non-activated cells maintained low spontaneous levels of activity at all times. Thus, the major output neurons of the hippocampus appear to be the neuroanatomical substrate for the large and rapidly developing neuronal plasticity induced by this classical conditioning paradigm.