Effect of the closed-loop hippocampal low-frequency stimulation on seizure severity, learning, and memory in pilocarpine epilepsy rat model.

AIMS: In this study, the anticonvulsant action of closed-loop, low-frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated. METHODS: Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test. RESULTS: Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre-ictal, ictal, and post-ictal periods. Meanwhile, DBS increased the post-ictal-to-pre-ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post-ictal-to-pre-ictal ratio of coherence. In addition, DBS increased the hippocampal-mPFC coupling in pre-ictal period and decreased the coupling in the ictal and post-ictal periods. CONCLUSION: Applying closed-loop, low-frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low-frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non-seizure state in subjects that received DBS.

Deep brain stimulation effects on learning, memory and glutamate and GABAA receptor subunit gene expression in kindled rats.

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 2­3 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 2­3 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.

The role of dopamine D2-like receptors in a "depotentiation-like effect" of deep brain stimulation in kindled rats.

The mechanisms involved in the anti-seizure effects of low-frequency stimulation (LFS) have not been completely determined. However, Gi-protein-coupled receptors, including D2-like receptors, may have a role in mediating these effects. In the present study, the role of D2-like receptors in LFS' anti-seizure action was investigated. Rats were kindled with semi-rapid (6 stimulations per day), electrical stimulation of the hippocampal CA1 area. In LFS-treated groups, subjects received four trials of LFS at 5 min, 6 h, 24 h, and 30 h following the last kindling stimulation. Each LFS set occurred at 5 min intervals, and consisted of 4 trains. Each train contained 200, 0/1 ms long, monophasic square wave pulses at 1 Hz. Haloperidol (D2-like receptors antagonist, 2 µm) and/or bromocriptine (D2-like receptors agonist 2 µg/µlit) were microinjected into the lateral ventricle immediately after the last kindling, before applying LFS. Obtained results showed that applying LFS in fully-kindled subjects led to a depotentiation-like decrease in kindling-induced potentiation and reduced the amplitude and rise slope of excitatory and inhibitory post-synaptic currents in whole-cell recordings from CA1 pyramidal neurons. In addition, LFS restored the kindling-induced, spatial learning and memory impairments in the Barnes maze test. A D2-like receptor antagonist inhibited these effects of LFS, while a D2-like receptor agonist mimicked these effects. In conclusion, a depotentiation-like mechanism may be involved in restoring LFS' effects on learning and memory, and synaptic plasticity. These effects depend on D2-like receptors activity.

Spatial Learning and Memory in Barnes Maze Test and Synaptic Potentiation in Schaffer Collateral-CA1 Synapses of Dorsal Hippocampus in Freely Moving Rats.

INTRODUCTION: Synaptic plasticity has been suggested as the primary physiological mechanism underlying memory formation. Many experimental approaches have been used to investigate whether the mechanisms underlying Long-Term Potentiation (LTP) are activated during learning. Nevertheless, little evidence states that hippocampal-dependent learning triggers synaptic plasticity. In this study, we investigated if learning and memory in the Barnes maze test are accompanied by the occurrence of LTP in Schaffer collateral to CA1 synapses in freely moving rats. METHODS: The rats were implanted with a recording electrode in stratum radiatum and stimulating electrodes in Schaffer collaterals of the CA1 region in the dorsal hippocampus of the right hemisphere. Following the recovery period of at least 10 days, field potentials were recorded in freely moving animals before and after training them in Barnes maze as a hippocampal-dependent spatial learning and memory test. The slope of extracellular field Excitatory Postsynaptic Potentials (fEPSPs) was measured before and after the Barnes maze test. RESULTS: The results showed that the fEPSP slope did not change after learning and memory in the Barnes maze test, and this spatial learning did not result in a change in synaptic potentiation in the CA1 region of the hippocampus. CONCLUSION: Spatial learning and memory in the Barnes maze test are not accompanied by LTP induction in Schaffer collateral-CA1 synapses.

Inhibition of microglia in the basolateral amygdala enhanced morphine-induced antinociception: Possible role of GABAA receptors.

In clinical medicine, morphine is widely used to relieve many types of pain, but it has several side effects such as the development of tolerance and dependence. In order to decrease the side effects of morphine administration for the treatment of pain, the combination of minocycline as a glial inhibitor and morphine has been suggested in previous studies. It is important to understand which synaptic mechanisms are involved in the potentiative effect of minocycline on morphine antinociception. To this aim, male Wistar rats were bilaterally cannulated in the basolateral amygdala by srereotaxic instrument. A tail-flick apparatus was used to measure the pain threshold. The results revealed that intraperitoneal injection of morphine (2.5-7.5 mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of minocycline (5-10 µg/rat) by itself had no effect on tail-flick latency, while the microinjection of the same doses of minocycline with an ineffective dose of morphine (5 mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of different doses of muscimol (0.001-0.005 µg/rat) increased the minocycline-induced potentioation on morphine response in the tail-flick test. Intra-basolateral amygdala microinjection of muscimol by itself had no effect on tail-flick latency. On the other hand, intra-basolateral amygdala microinjection of bicuculline (0.01-0.1 µg/rat) inhibited minocycline-induced potentiation of morphine antinociception. It should be noted that intra-basolateral amygdala bicucculine by itself had no effect on tail-flick latency. It can thus be concluded that intra-basolateral amygdala minocycline potentiates morphine response in the tail-flick test. Moreover, basolateral amygdala GABAergic system may be involved in the minocycline-induced potentiation of morphine response via GABAA receptors.