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Epileptic seizures are accompanied by learning and memory impairments. In this study, the effect of low frequency stimulation (LFS) on spatial learning and memory was assessed in kindled animals and followed for one month. Fully kindled rats received LFS at 4 times (immediately, 6 h, 24 h and 30 h following the final kindling stimulation). Applying LFS improved kindled animals' performance in the Barnes maze test. This LFS action was accompanied by a decrease in NR2B gene expression, an increase in the gene expression of the α subunit of calcineurin A and an increased NR2A/NR2B ratio in kindled animals. In addition, the gene expression of the GABAA receptor γ2 subunit increased at 2-3 h after applying LFS. The increase in NR2A/NR2B ratio was also observed 1 week after LFS. No significant changes were observed one month after LFS administration. Field potential recordings in the hippocampal CA1 area showed that kindling-induced potentiation of the field EPSP slope returned to near baseline when measured 2-3 h after applying LFS. Therefore, it may be postulated that applying LFS in kindled animals reduced the seizure-induced learning and memory impairments, albeit time-dependently. In tandem, LFS prevented kindling-induced alterations in gene expression of the described proteins, which are potentially important for synaptic transmission and/or potentiation. Moreover, a depotentiation-like phenomenon may be a possible mechanism underlying the LFS action. Epileptic seizures are accompanied by learning and memory impairments. In this study, the effect of low frequency stimulation (LFS) on spatial learning and memory was assessed in kindled animals and followed for one month. Fully kindled rats received LFS at 4 times (immediately, 6 h, 24 h and 30 h following the final kindling stimulation). Applying LFS improved kindled animals’ performance in the Barnes maze test. This LFS action was accompanied by a decrease in NR2B gene expression, an increase in the gene expression of the α subunit of calcineurin A and an increased NR2A/NR2B ratio in kindled animals. In addition, the gene expression of the GABAA receptor γ2 subunit increased at 2–3 h after applying LFS. The increase in NR2A/NR2B ratio was also observed 1 week after LFS. No significant changes were observed one month after LFS administration. Field potential recordings in the hippocampal CA1 area showed that kindling-induced potentiation of the field EPSP slope returned to near baseline when measured 2–3 h after applying LFS. Therefore, it may be postulated that applying LFS in kindled animals reduced the seizure-induced learning and memory impairments, albeit time-dependently. In tandem, LFS prevented kindling-induced alterations in gene expression of the described proteins, which are potentially important for synaptic transmission and/or potentiation. Moreover, a depotentiation-like phenomenon may be a possible mechanism underlying the LFS action.

Low frequency stimulation (LFS) has anticonvulsant effect and may restore the ability of long-term potentiation (LTP) to the epileptic brain. The mechanisms of LFS have not been completely determined. Here, we showed that LTP induction was impaired following in vitro epileptiform activity (EA) in hippocampal slices, but application of LFS prevented this impairment. Then, we investigated the involvement of α-adrenergic receptors in this effect of LFS. EA was induced by increasing the extracellular K+ concentration to 12 mM and EPSPs were recorded from CA1 neurons in whole cell configuration. EA increased EPSP amplitude from 6.9 ± 0.7 mV to 9.6 ± 0.6 mV. For LTP induction, the Schaffer collaterals were stimulated by high frequency stimulation (HFS; two trains of 100 pulses, 100 Hz at the interval of 20 s). The application of HFS resulted in 40.9 ± 2.3% increase in the amplitude of EPSPs. However, following EA, HFS could not produce any significant changes in EPSP amplitude. Administration of LFS (1 Hz, 900 pulses) to Schaffer collaterals at the beginning of EA restored LTP induction to the hippocampal slices and HFS increased the EPSPs amplitude up to 41.7 ± 3.1% of baseline. When slices were perfused by prazosin (α1-adrenergic receptor antagonist; 10 μM) before and during LFS application, LFS improvement on LTP induction was reduced significantly. Perfusion of slices by yohimbine (α2-adrenergic receptor antagonist; 5 μM) had no effect on LFS action. Therefore, it may be concluded that following epileptiform activity, LFS can improve the impairment of LTP generation through α1, but not α2, adrenergic receptor activity.

In addition to its anticonvulsant effect, low frequency stimulation (LFS) improves learning and memory in kindled animals. In the present study, the role of 5-HT 1A receptors in mediating LFS’ improving effect on spatial learning and memory was investigated in amygdala-kindled rats. Amygdala kindling was conducted in a semi-rapid kindling stimulations (12 stimulations per day) in male Wistar rats. LFS (4 trains of 0.1 ms pulse duration at 1 Hz, 200 pulses, 50–150 μA, at 5 min intervals) was applied after termination of kindling stimulations. NAD-299 (a selective 5-HT 1A receptor antagonist; 2.5 and 5 μg/μl) was microinjected into the hippocampal CA1 before applying LFS. The Morris water maze, and novel object recognition tests were conducted after the last kindling stimulation. Hippocampal samples were also prepared, and 5-HT 1A receptor gene expression levels were assessed using quantitative RT-PCR. In kindled animals, LFS reduced impairments in spatial learning and memory in the Morris water maze and novel object recognition tests. Microinjection of NAD doses of 5 μg/μl reduced the effects of LFS on learning and memory. The gene expression level of 5-HT 1A receptors increased significantly in the hippocampus of amygdala-kindled rats. However, LFS applied after kindling stimulations inhibited this effect. It seems that activation of 5-HT 1A receptors in the CA1 field is necessary for LFS’ improving effects on spatial learning and memory in kindled animals; although surprisingly, LFS application prevented the elevation in gene expression of 5-HT 1A receptors in kindled animals. © 2019 Elsevier Inc.

Aim: Low frequency stimulation (LFS) inhibits neuronal hyperexcitability following epileptic activity. However, knowledge about LFS' inhibitory mechanisms is lacking. Here, α1 and α2 adrenergic receptors' roles in mediating LFS inhibitory action on high-K+ induced epileptiform activity (EA) was examined in rat hippocampal slices.Materials and methods: LFS (1 Hz, 900 pulses) was applied to the Schaffer collaterals. Whole-cell, patch clamp recording was used to measure changes in CA1 pyramidal neurons' excitability. By applying high-K+ on hippocampal slices, EA was induced, and neuronal excitability increased.Results: When administered at the beginning of EA, LFS reduced neuronal excitability. In the presence of prazosin (10 µM, an α1 adrenergic receptor antagonist) and yohimbine (5 µM, an α2 adrenergic receptor antagonist), LFS' typically has a restorative impact on EA-induced membrane potential hyperpolarization and spike firing frequency, but this effect was reduced after high-K+ washout; These antagonists did not have a significant effect on LFS' inhibitory action on spike firing during EA.Conclusion: These findings suggest that LFS' anticonvulsant effect, on neuronal hyperexcitability following high-K+ EA, may be mediated partly through α adrenergic receptors in hippocampal slices.

Low frequency stimulation (LFS) has been proposed as a method in the treatment of epilepsy, but its anticonvulsant mechanism is still unknown. In the current study, the hippocampal CA1 region was microinjected with NAD-299 (a selective 5-HT1A antagonist), and its role in mediating the inhibitory action of LFS on amygdala kindling was investigated. Male Wistar rats were kindled by amygdala stimulation in a semi-rapid kindling manner (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, 50–150 μA) was applied at 5 min after termination of daily kindling stimulations. NAD (a selective 5-HT1A antagonist) was microinjected into the CA1 region of the hippocampus at the doses of 2.5 and 5 μg/1 μl. An open field test was also run to determine the motor activity of animals in different experimental groups. The application of LFS following daily kindling stimulations reduced the behavioral seizure stages, afterdischarge duration, and stage 5 seizure duration and increased the latency to stage 4 seizure compared to the kindled group. However, microinjection of NAD at the doses of 5 μg/1 μl, but not 2.5 μg/1 μl, blocked the inhibitory effect of LFS on behavioral and electrophysiological parameters in kindled animals. It could be presumed that 5-HT1A receptors in the CA1 area are involved in mediating the antiepileptic effects of LFS.

Anxiety is prevalent in asthma, and is associated with disease severity and poor quality of life. However, no study to date provides direct experimental evidence for the effect of allergic inflammation on the structure and function of medial prefrontal cortex (mPFC) and amygdala, which are essential regions for modulating anxiety and its behavioral expression. We assessed the impact of ovalbumin (OVA)-induced allergic inflammation on the appearance of anxiety-like behavior, mPFC and amygdala volumes using MRI, and the mPFC-amygdala circuit activity in sensitized rats. Our findings exhibited that the OVA challenge in sensitized rats induced anxiety-like behavior, and led to more activated microglia and astrocytes in the mPFC and amygdala. We also found a negative correlation between anxiety-like behavior and amygdala volume. Moreover, OVA challenge in sensitized rats was associated with increases in mPFC and amygdala activity, elevation of amygdala delta-gamma coupling, and the enhancement of functional connectivity within mPFC-amygdala circuit – accompanied by an inverted direction of information transferred from the amygdala to the mPFC. We indicated that disrupting the dynamic interactions of the mPFC-amygdala circuit may contribute to the induction of anxiety-related behaviors with asthma. These findings could provide new insight to clarify the underlying mechanisms of allergic inflammation-induced psychiatric disorders related to asthma.

The Inhibitory effect of electrical low-frequency stimulation (LFS) on neuronal excitability and seizure occurrence has been indicated in experimental models, but the precise mechanism has not established. This investigation was intended to figure out the role of α1 and α2 adrenergic receptors in LFS' inhibitory effect on neuronal excitability. Epileptiform activity induced in an in vitro rat hippocampal slice preparation by high K+ ACSF and LFS (900 square wave pulses at 1 Hz) was administered at the beginning of epileptiform activity to the Schaffer collaterals. In CA1 pyramidal neurons, the electrophysiological properties were measured at the baseline, before high K+ ACSF washout, and at 15 min after high K+ ACSF washout using whole-cell, patch-clamp recording. Results indicated that after high K+ ACSF washout, prazosine (10 µM; α1 adrenergic receptor antagonist) and yohimbine (5 µM; α2 adrenergic receptor antagonist) suppressed the LFS’ effect of reducing rheobase current and utilization time following depolarizing ramp current, the latency to the first spike following a depolarizing current and latency to the first rebound action potential following hyperpolarizing current pulses. Thus, it may be proposed that LFS’ inhibitory action on the neuronal hyperexcitability, in some way, is mediated by α1 and α2 adrenergic receptors.

Allergic rhinitis (AR) is a chronic inflammatory disease frequently associated with a deficit in learning and memory. Working memory is an important system for decision making and guidance, which depends on interactions between the ventral hippocampus (vHipp) and the prelimbic prefrontal cortex (plPFC). It is still unclear whether AR influences the activity and coupling of these brain areas, which consequently may impair working memory. The current study aimed to examine alterations of the vHipp-plPFC circuit in a rat model of AR. Our results show decreased working memory performance in AR animals, accompanied by a reduction of theta and gamma oscillations in plPFC. Also, AR reduces coherence between vHipp and plPFC in both theta and gamma frequency bands. Cross-frequency coupling analyses confirmed a reduced interaction between hippocampal theta and plPFC gamma oscillations. Granger causality analysis revealed a reduction in the causal effects of vHipp activity on plPFC oscillations and vice versa. A significant correlation was found between working memory performance with disruption of functional connectivity in AR animals. In summary, our data show that in AR, there is a deficit of functional coupling between hippocampal and prefrontal network, and suggest that this mechanism might contribute to working memory impairment in individuals with AR.

Low frequency stimulation (LFS) has inhibitory effect on hyperexcitability during epileptic states. However, knowledge is lacking about LFS patterns that can exert an optimal antiepileptic effect. In this study, the effect of different numbers of pulses and current intensities of 1 Hz LFS applied at various time points of epileptiform activity was evaluated in high-K+ model of epileptiform activity (EA). LFS was applied to the Schaffer collaterals, and changes in the excitability of CA1 pyramidal neurons were measured using whole-cell patch-clamp recording. Six hundred and 900 pulses of LFS at two current intensities (equal to and 1.5 times greater than the current intensity sufficient to elicit a 5 mV EPSP) administered at the beginning of EA revealed a stronger LFS inhibitory effect on EA-induced neuronal hyperexcitability when applied at higher pulse number and current intensity. LFS900 (high intensity) significantly hyperpolarized the membrane potential after a high-K+ ACSF washout, reduced the frequency of spontaneous action potentials during EA, and attenuated neuronal firing frequency after high-K+ ACSF washout. Moreover, applying LFS900 (high intensity) before EA induction and 8–10 min after EA initiation could not significantly affect neuronal hyperexcitability, compared to its application at the beginning of EA. This study’s findings also offered long-term depression (LTD) as a probable mechanism for LFS’ inhibitory role on EA-induced neuronal hyperexcitability. Therefore, the application of LFS (1 Hz) at 900 pulses and greater current intensity at the beginning of EA can exert a strong inhibitory effect on EA-induced neuronal hyperexcitability.