Constantine Pavlides

Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of θ-rhythm ☆

Abstract Long-term potentiation (LTP), a long lasting enhancement of synaptic efficacy is considered a model for learning and memory. In anesthetized rats, θ-rhythm was induced in the dentate gyrus by midbrain stimulation. Short trains of pulses were applied to the perforant pathway either at the peak of θ-rhythm or its trough. Trains applied at the peak of θ-rhythm induced LTP while trains applied at the trough produced a decrease of synaptic efficacy or had no effect. Thus, θ-rhythm may play a modulating role in the induction of LTP, suggesting a possible mnemonic function for the rhythm during the behaviors in which it occurs.

Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation

Studies were performed in vivo on the dentate gyrus to investigate the possible involvement of Type I and Type II adrenal steroid receptors in the mediation of reported adrenal steroid effects on long-term potentiation, through the use of specific Type I and Type II receptor agonists and antagonists. In adrenalectomized rats, administration of aldosterone, a specific Type I agonist, produced a marked enhancement in long-term potentiation, in comparison to either the adrenalectomized or sham adrenalectomized controls. Administration of RU 28318, a Type I antagonist, which by itself had minimal effects, blocked the aldosterone enhancement. In contrast, administration of the specific Type II agonist, RU 28362, produced a marked decrement in the induction of long-term potentiation. The RU 28362 effect was blocked by a prior injection of the Type II antagonist, RU 38486. Neither adrenalectomy nor administration of any of the steroid agonists or antagonists had noticeable effects on neuronal excitability (as determined by the field potentials), nor on post-tetanic potentiation. These findings are consistent with other studies that have shown a biphasic effect of increasing levels of corticosterone on long-term or prime burst potentiation. Taken together, these studies suggest that Type I receptors, with a high affinity for corticosterone, and Type II receptors, having a lower affinity for corticosterone, form a two-level recognition system to modulate induced synaptic plasticity in opposite directions in the dentate gyrus and possibly also in Ammons horn.

Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices.

We previously demonstrated in the dentate gyrus (DG) of anesthetized and freely behaving rats that both acute as well as chronic administration of corticosterone produces a suppression in long-term potentiation (LTP). In subsequent studies we showed, again in the DG, that activation of the two types of adrenal steroid receptors (mineralocorticoid (MR) and glucocorticoid (GR)) produce biphasic effects on synaptic plasticity; activation of MR produces an enhancement while activation of GR produces a suppression in LTP. In a separate study, we further demonstrated in rats administered the specific GR agonist RU 28362 that high-frequency stimulation, which normally produces LTP, instead produced long-term depression (LTD) in these animals. In the present study we investigated the effects of MR and GR activation by adrenal steroids on synaptic plasticity of the hippocampal CA1 field, but we studied this ex vivo, in a slice preparation. The results indicate that, as in our studies in the DG, adrenal steroids produce biphasic effects: in ADX rats, aldosterone (a specific MR agonist) enhanced while RU 28362 suppressed synaptic plasticity. Unlike the in vivo preparation, however, rarely was LTD observed in the animals receiving RU 28362. Also, ADX itself did not produce noticeable effects on synaptic plasticity. The present results are in agreement with previous studies showing that elevations in corticosterone or an acute episode of experimentally induced stress in vivo causes a suppression in LTP in the hippocampal CA1 field, in vitro.

Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery.

Chronic stress has been shown in animal models to result in altered dendritic morphology of pyramidal neurons of the medial prefrontal cortex (mPFC). It has been hypothesized that the stress-induced dendritic retractions and spine loss lead to disrupted connectivity that results in stress-induced functional impairment of mPFC. While these alterations were initially viewed as a neurodegenerative event, it has recently been established that stress induced dendritic alterations are reversible if animals are given time to recover from chronic stress. However, whether spine growth accompanies dendritic extension remains to be demonstrated. It is also not known if recovery-phase dendritic extension allows for re-establishment of functional capacity. The goal of this study, therefore, was to characterize the structural and functional effects of chronic stress and recovery on the infralimbic (IL) region of the rat mPFC. We compared neuronal morphology of IL layer V pyramidal neurons from male Sprague-Dawley rats subjected to 21 days of chronic restraint stress (CRS) to those that experienced CRS followed by a 21 day recovery period. Layer V pyramidal cell functional capacity was assessed by intra-IL long-term potentiation (LTP) both in the absence and presence of SKF38393, a dopamine receptor partial agonist and a known PFC LTP modulator. We found that stress-induced IL apical dendritic retraction and spine loss co-occur with receptor-mediated impairments to catecholaminergic facilitation of synaptic plasticity. We also found that while post-stress recovery did not reverse distal dendritic retraction, it did result in over extension of proximal dendritic arbors and spine growth as well as a full reversal of CRS-induced impairments to catecholaminergic-mediated synaptic plasticity. Our results support the hypothesis that disease-related PFC dysfunction is a consequence of network disruption secondary to altered structural and functional plasticity and that circuitry reestablishment may underlie elements of recovery. Accordingly, we believe that pharmacological treatments targeted at preventing dendritic retraction and spine loss or encouraging circuitry re-establishment and stabilization may be advantageous in the prevention and treatment of mood and anxiety disorders.

Lonf-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulse of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity of the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occurring theta rhythm may play a modulatory role in the induction of LTP.

Hippocampal homosynaptic long-term depression/depotentiation induced by adrenal steroids

The effects of adrenal steroids on synaptic plasticity were investigated in the dentate gyrus of the hippocampus. Experiments were performed in either adrenalectomized or intact (non-adrenalectomized), anesthetized rats. High-frequency stimulation was applied to the medial perforant pathway at three different frequencies; 100, 200 or 400 Hz, either post- or pre- and post-administration of the specific Type-II adrenal steroid receptor agonist RU 28362. High-frequency stimulation prior to RU 28362 administration produced a frequency-dependent long-term potentiation of the population spike, with 100 Hz showing no long-term potentiation and 400 Hz the highest degree of potentiation. In contrast, following administration of RU 28362, high-frequency stimulation produced a long-term depression (in comparison to baseline). In the experiments in which high-frequency stimulation was applied both pre- and post-RU 28362 administration, the size of the population spike was initially potentiated and then depotentiated after the RU 28362 injection. This effect was also frequency dependent, although opposite to the long-term potentiation effect. That is, 400 Hz was the least effective frequency for inducing long-term depression/depotentiation, while 100 Hz was the most effective. Long-term depression/depotentiation was immediate following high-frequency stimulation and lasted for the extent of the recording session, in some cases longer than 1 h. Similar to the finding reported in the accompanying paper, induction of long-term potentiation was substantially suppressed by RU 28362. However, in a number of experiments long-term potentiation could still be induced after RU 28362 administration, even after long-term depression/depotentiation had been established. In these cases, stimulation at the higher frequencies was necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo.

Nicotinic acetylcholine receptors (nAChRs) affect a wide array of biological processes, including learning and memory, attention, and addiction. lynx1, the founding member of a family of mammalian prototoxins, modulates nAChR function in vitro by altering agonist sensitivity and desensitization kinetics. Here we demonstrate, through the generation of lynx1 null mutant mice, that lynx1 modulates nAChR signaling in vivo. Its loss decreases the EC(50) for nicotine by approximately 10-fold, decreases receptor desensitization, elevates intracellular calcium levels in response to nicotine, and enhances synaptic efficacy. lynx1 null mutant mice exhibit enhanced performance in specific tests of learning and memory. Consistent with reports that mutations resulting in hyperactivation of nAChRs can lead to neurodegeneration, aging lynx1 null mutant mice exhibit a vacuolating degeneration that is exacerbated by nicotine and ameliorated by null mutations in nAChRs. We conclude that lynx1 functions as an allosteric modulator of nAChR function in vivo, balancing neuronal activity and survival in the CNS.

Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimers disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nm. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3′-O-methyl-epicatechin-5-O-β-glucuronide (3′-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3′-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

Single-unit activity in the lateral nucleus of the amygdala and overlying areas of the striatum in freely behaving rats: rates, discharge patterns, and responses to acoustic stimuli.

Acoustic responses of single units were examined in awake, freely behaving rats in the lateral nucleus of the amygdala (AL). Recordings were made from a movable bundle of 9 microwires. Most cells had very low rates of spontaneous activity (about 3 spikes/s average). Firing rates increased during sleep states. Short-latency auditory responses (12-25 ms) were found in the dorsal subnucleus (ALd) of the AL. Cells in the ALd most typically responded in a sustained fashion. Some of the cells in the ALd showed preferences for high frequencies, tone bursts, or frequency-modulated stimuli with center frequencies above 12 kHz. Response latencies were considerably longer in other areas of the amygdala. Our results corroborate the main findings of a previous study (F. Bordi & J. LeDoux, 1992) that examined the acoustic response properties of single cells in the AL in anesthetized rats. Together the findings from awake and anesthetized rats provide the most precise information about sensory processing in amygdala neurons available to date.

Effects of mineralocorticoid and glucocorticoid receptors on long-term potentiation in the CA3 hippocampal field.

We have previously shown that the two types of adrenal steroid receptors, mineralocorticoid MR. and glucocorticoid GR. produce opposite effects on long-term potentiation LTP. in the dentate gyrus in vivo. and CA1 hippocampal field in vitro. More specifically, MR activation enhanced and prolonged LTP, whereas GR activation suppressed LTP in these areas and also produced a long-term depression LTD. of the synaptic response. In the present experiment we investigated acute effects of MR and GR activation on LTP induction in the mossy fiber and commissural associational input to the CA3 hippocampal field, since the mechanisms underlying LTP induction in these two pathways differ, the former being N-methyl-D-aspartate receptor NMDAR. independent while the latter being NMDAR-dependent. Rats were either adrenalectomized ADX or adrenally intact. ADX animals were acutely injected with either the specific MR agonist, aldosterone, the specific GR agonist RU 28362 or vehicle. One hour following the injection, the animals were prepared for electrophysiological recording stimulation. Field potential recordings were performed in the radiatum or laconosum moleculare layers of the CA3 field, with stimulation of either the mossy fibers or the commissural associational input from the contralateral hemisphere. We also replicated our previous findings by recording in the dentate gyrus with stimulation of the medial perforant pathway, in the same animals. As observed in our previous study in the dentate gyrus, we found an enhancement and a suppression of LTP with MR and GR activation, respectively. Similarly, for the commissural associational input to CA3, MR activation enhanced LTP, while GR activation reduced it. In contrast, for the mossy fiber input to CA3, neither MR nor GR activation significantly affected LTP induction. These results indicate that adrenal steroids may modulate LTP induction in the hippocampus via an interaction with glutamatergic NMDAR.