The role of glutamate NMDA receptors of the mediodorsal thalamus in scopolamine-induced amnesia in rats.

The current study was designed to examine the role of glutamate NMDA receptors of the mediodorsal thalamus (MD) in scopolamine-induced memory impairment. Adult male rats were bilaterally cannulated into the MD. According to the results, intraperitoneal (i.p.) administration of scopolamine (1.5 mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the glutamate NMDA receptors agonist, N-Methyl-D-aspartic acid (NMDA; 0.05 µg/rat), into the MD significantly improved scopolamine-induced memory consolidation impairment. Co-administration of D-AP5, a glutamate NMDA receptor antagonist (0.001-0.005 µg/rat, intra-MD) potentiated the response of an ineffective dose of scopolamine (0.5 mg/kg, i.p.) to impair memory consolidation, mimicking the response of a higher dose of scopolamine. Noteworthy, post-training intra-MD microinjections of the same doses of NMDA or D-AP5 alone had no effect on memory consolidation. Moreover, the blockade of the glutamate NMDA receptors by 0.003 ng/rat of D-AP5 prevented the improving effect of NMDA on scopolamine-induced amnesia. Thus, it can be concluded that the MD glutamatergic system may be involved in scopolamine-induced memory impairment via the NMDA receptor signaling pathway.

The effects of kindling during pregnancy on long-term potentiation (LTP) induction and M1 muscarinic acetylcholine receptors in male rat offspring.

Background and purpose: Neonates of pregnant women with epilepsy may compromise normal neurodevelopment and hippocampal morphology. Memory and learning disorders and a decrease in verbal IQ scores are seen in these children later in life. In the previous study, we suggested that the central muscarinic cholinergic receptors had an important role in learning and memory deficits induced by prenatal pentylenetetrazol-kindling in pups born to kindled mothers. This study aimed to investigate the effects of kindling during pregnancy on long-term potentiation (LTP) induction and the role of M1 muscarinic acetylcholine receptors in the hippocampus of male offspring. Experimental approach: Twenty female Wistar rats were divided into two groups on the 13th day of their gestation (kindled and control; n = 10). Animals in the first group were kindled by i.p. injections of 25 mg/kg body weight pentylenetetrazol every 15 min until seizures occurred and the control group received normal saline. The effect of maternal seizures and perfusion of specific M1 muscarinic receptors antagonist (telenzepine at doses of 0.01, 0.1, and 1 nmol) on the LTP induction of 80 pups were tested at 12 weeks of age by field potential recordings. Findings/Results: The results of the electrophysiological study revealed that recurrent seizures during pregnancy impaired field excitatory postsynaptic potentials (fEPSP)-LTP induction and normal development of M1 muscarinic receptors in the hippocampus of male offspring. Also, the results demonstrated that maternal seizure did not significantly affect the paired-pulse indexes and population spike-LTP in the hippocampus of male offspring. Conclusion and implications: Our study showed that recurrent seizures during pregnancy cause impaired fEPSP-LTP induction and abnormal development of the M1 muscarinic receptor in the hippocampus.

Hippocampal orexin-1 and endocannabinoid-1 receptors underlie the kainate-induced occlusion in theta-burst long- term potentiation.

INTRODUCTION: Seizures may result from the hyperexcitable neuronal activity of the brain. Multiple neurotransmitter receptors, including orexin (OX) and endocannabinoids interfere with forming the synaptic responses linked to the seizures. Therefore, this study investigates the involvement of OX-1 (OX1R) and endocannbinoid-1 (CB1R) receptors in the kainate- induced excitability in the synaptic field responses. MATERIAL AND METHODS: Theta pattern used to stimulate Schaffer collaterals and then metal microelectrodes to record the CA1 field excitatory postsynaptic potentials (fEPSPs). Input/ output stimulation and responses and paired- pulse (PP) stimuli employed to measure the state of synaptic activity in normal and kainate- induced seizure-like hyperexcitable activities and the slope of fEPSPs used as a measure of the change in the synaptic activity. Furthermore, agonists and antagonists of OX and endocannabinoids infused to investigate the involvement of their receptors. RESULT: The results showed that kainate application increased the fEPSP slope either in input stimuli with different intensities/output synaptic responses (I/O), or test pulse stimulated baseline synaptic responses (BSR) and, hence, increased the excitability of field responses in the CA1 region. However, neither kainate nor theta burst stimulation (TBS) could alter the PP stimuli -induced synaptic responses. TBS increased the fEPSP slope of the kainate-applied I/O and BSR, however, the increase was not high enough in BSR to be classified as long-term potentiation (LTP). The single-antagonist OX1R and CB1R administration prevented TBS- induced potentiation and partially recovered the effect by adding eCB or OX agonists in kainate-injected animals. In contrast, OX or combined eCB-OX antagonist application group demonstrated nearly full recovery of LTP induction. CONCLUSION: Our study concludes that blockade of OX1 or CB1 prevents the induction of LTP, and OX infusion or both receptor blockade recovers the LTP.

Nandrolone improve synaptic plasticity at the hippocampus CA1 area and spatial localization in the Morris water maze of male adolescent rats.

Nandrolone is the most popular compound that are mainly abused. Experimental studies have reported that administration of nandrolone affects cognitive performance. So, the aim of this study is to evaluate the effect of nandrolone on spatial localization and synaptic plasticity of male adolescent rats. Experimantal groups received DMSO and nandrolone (10, 30 and 60 µg, i.c.v.). Another aim is to evaluate the role of castration on spatial learning and memory changes induced by nandrolone. Therefore, the rats of fifth and sixth groups were castrated and received DMSO or nandrolone. Analysis showed that escape latency and traveled distance in the group which received nandrolone (60 µg) were significantly lower than control group. Also, the escape latency and traveled distance in the group of castration which received nandrolone was significantly higher than nandrolone treated group. The results of field potential recording showed that fEPSP-LTP in nandrolone-treated group was higher than DMSO-treated group. The magnitude of fEPSP-LTP in the group of castration which received nandrolone was significantly lower than nandrolone-treated group. The results demonstrated that nandrolone improved spatial learning, but castration could abolished nandrolone-induced spatial learning improvement. These results indicating that at least some effect of nandrolone on learning induced through changes in gonadal function.

Calcineurin is involved in retrieval of passive avoidance memory and synaptic plasticity impairment induced by Nandrolone administration in adolescent male rats.

In spite of evidence about negative effects of Nandrolone Decanoate (ND) on cognitive and memory performance, the underlying mechanisms are complex and have remained unclear. This research examines the role of Calcineurin in synaptic plasticity and memory storage impairment in ND administrated adolescent male rats. For behavioral study by passive avoidance learning and memory (PAL), adolescent male rats were treated with ND or ND plus selective Calcineurin antagonist (Tacrolimus), before retention test. ND significantly decreased the retrieval of PAL, whereas Tacrolimus plus ND had no significant effect on PAL. For electrophysiological study hippocampal slices were perfused by ND or ND plus Tacrolimus. The magnitude of fEPSP-LTP of ND perfused slices was less than the control and a reduction of fEPSP-PS (E-S) coupling was observed, while pre-administration of Tacrolimus abolished the ND impairment effect on fEPSP-LTP and E-S coupling. This study showed that ND may induce impairing effects on hippocampal area CA1 activity and plasticity and PAL memory storage through changes in the function of the Calcineurin.

Nandrolone administration abolishes hippocampal fEPSP-PS potentiation and passive avoidance learning of adolescent male rats.

Despite the chronic effects of nandrolone decanoate (ND), the acute effects of ND on passive avoidance learning (PAL) and memory and its mechanism have not been investigated. This research examines the acute effect of ND on PAL, CA1 synaptic plasticity, testosterone and corticosterone serum levels, and the role of androgenic receptors (ARs). Adolescent male rats were treated with ND, 30 min before training and retention and after training test. AR antagonist was applied 15 min before ND. Hippocampal slices were perfused by ND. ND administration had an inverted U-shape effect on acquisition of PAL and on testosterone and corticosterone serum levels. The consolidation was only affected by high dose of ND. ND significantly decreased the retention of PAL across all doses. The magnitude of field excitatory postsynaptic potential long term potentiation was lower than that of control slices. In addition, an attenuation of field excitatory postsynaptic potential population spike coupling was also observed. Nilutamide could nullify the ND impairment effect. We concluded although a single dose of ND could affect all stages of PAL, its effects were more potent on retrieval, possibly arising from the acute effect of ND on the alterations of CA1 synaptic plasticity. In addition, ND may induce its effects directly through ARs and indirectly through plasma testosterone and corticosterone.

Prepubertal castration-associated developmental changes in sigma-1 receptor gene expression levels regulate hippocampus area CA1 activity during adolescence.

The functional relevance of sigma-1 (σ1 ) receptor expression in the rat hippocampal CA1 during adolescence (i.e., 35-60 days old) was explored. A selective antagonist for the σ1 receptor subtype, BD-1047, was applied to study hippocampal long-term potentiation (LTP) and spatial learning performance. Changes in the expression of the σ1 receptor subtype and its function were compared between castrated and sham-castrated rats. Castration reduced the magnitude of both field excitatory postsynaptic potential (fEPSP)-LTP and population spike (PS)-LTP at 35 days (d). BD-1047 decreased PS-LTP in sham-castrated rats, whereas BD-1047 reversed the effect of castration on fEPSP-LTP at 35 d. In addition, BD1047 impaired spatial learning and augmented σ1 receptor mRNA levels in castrated rats at 35 d. Surprisingly, neither castration nor BD1047 had an effect on fEPSP-LTP and PS-LTP, spatial learning ability or gene expression levels at 45 d. Castration had no effect on fEPSP-LTP but reduced PS-LTP at 60 d. BD1047 increased the magnitude of fEPSP-LTP, but had no effect on PS-LTP in castrated rats at 60 d. However, BD1047 reduced spatial learning ability, and σ1 receptor mRNA levels were decreased in castrated rats at 60 d. This study shows that σ1 receptors play a role in the regulation of both CA1 synaptic efficacy and spatial learning performance. The regulatory role of σ1 receptors in activity-dependent CA1-LTP is locality- and age-dependent, whereas its role in spatial learning ability is only age-dependent. Prepubertal castration-associated changes in the expression and function of the σ1 receptor during adolescence may play a developmental role in the regulation of hippocampal area CA1 activity and plasticity. © 2016 Wiley Periodicals, Inc.

Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons.

The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti-nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity.

Pre-pubertal castration improves spatial learning during mid-adolescence in rats.

Hippocampus functions, including spatial cognition and stress responses, mature during adolescence. In addition, hippocampus neuronal structures are modified by circulating sex steroids, which dramatically increase during adolescence. Therefore, the effects of castration and the circulating levels of the main sex steroid testosterone on spatial learning and memory were examined across postnatal ages to test whether pre-pubertal castration affected rats' spatial ability in the Morris Water maze (MWM). Male rats were either castrated or sham-castrated at 22d (days of age), or left gonadally intact. They were then trained and tested in the MWM beginning at 28d, 35d, 45d or 60d. We found that all of the intact rats learned the spatial task; however, the males at 22d and 28d required more trials to acquire the task than the males at older ages. The males castrated at 22d and tested at 35d had significantly lower escape latency and traveled distance during training than the sham-castrated males trained at the same age. No differences were observed in mean values of escape latency and traveled distance at 45d even though they had comparable levels of testosterone. We conclude that adult-typical performance for male spatial memory emerges during mid-adolescence and that pre-pubertal castration appears to improve spatial learning during this time.

Intra-hippocampal injection of lipopolysaccharide inhibits kindled seizures and retards kindling rate in adult rats.

Neuroinflammation facilitates seizure acquisition and epileptogenesis in developing brain. Yet, the studies on impact of neuroinflammation on mature brain epileptogenesis have led to inconsistent results. Hippocampus is particularly vulnerable to damage caused by ischemia, hypoxia and trauma, and the consequent neuroinflammation, which can lead in turn to epilepsy. Lipopolysaccharide (LPS) is extensively used in experimental studies to induce neuroinflammation. In this study, effect of acute and chronic intra-CA1 infusion of LPS on amygdala-kindled seizures and epileptogenesis was examined in mature rats. LPS (5 µg/rat) inhibited evoked amygdala afterdischarges and behavioral seizures. Anticonvulsant effect of LPS was observed 0.5 h after administration and continued up to 24 h. This effect was accompanied by intra-hippocampal elevation of nitric oxide (NO), interleukin1-ß, and tumor necrosis factor-α and was prevented by microglia inhibitor, naloxone, NO synthase inhibitor, Nω-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, piroxicam, and interleukin1-ß receptor antagonist, interleukin1-ra. Moreover, daily intra-hippocampal injection of LPS significantly retarded kindling rate. In order to further elucidate the effect of LPS on synaptic transmission and short-term plasticity, changes in field excitatory postsynaptic potentials and population spikes were measured in stratum radiatum and stratum pyramidale of LPS-treated kindled rats. LPS impaired baseline synaptic transmission in hippocampal Schaffer collateral-CA1 synapse and reduced the magnitude of paired-pulse facilitation. Our results suggest that direct suppression of presynaptic mechanisms in Schaffer collateral-CA1 synapses, as well as the inflammatory mediators released by LPS in the hippocampus, is involved in antiepileptic effect of LPS.

Prepubertal castration causes the age-dependent changes in hippocampal long-term potentiation.

The effects of prepubertal castration on hippocampal CA3-CA1 synaptic transmission and plasticity were studied at different ages in vitro. The field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were simultaneously recorded from stratum radiatum and stratum pylamidale of area CA1 following stimulation of Schaffer collaterals in slices taken from sham-castrated and castrated rats at postnatal days (PND) 28, 35, 45, and 60. Castration had no effect on baseline responses at different ages except at PND 60 that a decrease in the fEPSP slope was seen. Prepubertal castration caused age-specific changes in CA1-long term potentiation (LTP) induction. The castration did decrease both fEPSP-LTP and PS-LTP at PND 35 but a decrease was seen only in PS-LTP at PND 60. NMDA receptor antagonist AP5 (25 µM) completely blocked both fEPSP-LTP and PS-LTP at PND 60 and only PS-LTP at PND 35 in both sham-castrated and castrated groups. Although AP5 blocked fEPSP-LTP at PND 35 in sham-castrated group, it failed to inhibit fEPSP-LTP at PND 35 in castrated one. These findings suggest that prepubertal castration causes the age-dependent changes in CA1-LTP induction, which might arise from alterations in the NMDA receptors.

Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats.

Neurohormones like testosterone and estrogen have an important role in learning and memory. Many biological effects of androgens in the brain require the local conversion of these steroids to an estrogen. The current research has conducted to assess the effect of testosterone, estrogen and aromatase inhibitor (anastrozole) on spatial discrimination of rats, using Morris water maze and also the pathway of the effect of testosterone by using anastrozole. Adult male rats were bilaterally cannulated into CA1 region of hippocampus and divided into 15 groups. Different groups received DMSO 0.5 microl and DMSO 0.5 microl + DMSO 0.5 microl as control groups and different doses of testosterone enanthate (TE) (20, 40 and 80 microg/0.5 microl), estradiol valerat (EV) (1, 2.5, 5, 10, and 15 microg/0.5 microl), anastrozole (An) (0.25, 0.5, 1 microg/0.5 microl), TE 80 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl and EV 15 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl all days before training. TE and EV were injected 30-35 min before training and anastrozole was injected 25-30 min before training. Our results have shown both TE 80 microg/0.5 microl and EV 15 microg/0.5 microl groups increase in escape latency and traveled distance to find invisible platform. Also we have shown that anastrozole dose dependently decreases escape latency and traveled distance. We resulted that both TE and EN impaired acquisition of spatial learning and memory but anastrozole improved it. Anastrozole also could be buffered TE-induced impairment effect but not EV.