Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus.

Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead.

Effects of chronic administration of melatonin on spatial learning ability and long-term potentiation in lead-exposed and control rats.

OBJECTIVE: To explore the changes in spatial learning performance and long-term potentiation (LTP) which is recognized as a component of the cellular basis of learning and memory in normal and lead-exposed rats after administration of melatonin (MT) for two months. METHODS: Experiment was performed in adult male Wistar rats (12 controls, 12 exposed to melatonin treatment, 10 exposed to lead and 10 exposed to lead and melatonin treatment). The lead-exposed rats received 0.2% lead acetate solution from their birth day while the control rats drank tap water. Melatonin (3 mg/kg) or vehicle was administered to the control and lead-exposed rats from the time of their weaning by gastric gavage each day for 60 days, depending on their groups. At the age of 81-90 days, all the animals were subjected to Morris water maze test and then used for extracellular recording of LTP in the dentate gyrus (DG) area of the hippocampus in vivo. RESULTS: Low dose of melatonin given from weaning for two months impaired LTP in the DG area of hippocampus and induced learning and memory deficit in the control rats. When melatonin was administered over a prolonged period to the lead-exposed rats, it exacerbated LTP impairment, learning and memory deficit induced by lead. CONCLUSION: Melatonin is not suitable for normal and lead-exposed children.

Muscarinic cholinergic modulation of synaptic transmission and plasticity in rat hippocampus following chronic lead exposure.

The cholinergic system is believed to be associated with learning and memory functions. Lead (Pb2+) is a well-known neurotoxic metal that causes irreversible damage to the central nervous system (CNS). To investigate whether Pb2+ interferes with cholinergic modulation, we examined the effects of carbachol (CCh), a muscarinic cholinergic agonist, on synaptic transmission and plasticity in the CA1 area of the hippocampus of developmentally Pb2+-exposed rats. The results showed that: (1) In both control and Pb2+-exposed rats, 0.1 microM CCh significantly enhanced tetanus-induced long-term potentiation (LTP), while 5 microM CCh induced a reversible depression of field excitatory postsynaptic potentials (fEPSPs). However, both the enhancement of LTP and depression of fEPSPs were significantly smaller in Pb2+-exposed rats than in controls, suggesting that the extent of the effect of CCh on the cholinergic system was depressed by Pb2+. (2) In Pb2+-exposed rats, the enhancement of LTP induced by 0.1 microM CCh was attenuated by pirenzepine, a M1AChR antagonist, but was not affected by methoctramine tetrahydrochloride (M-105), a M2/4AChR antagonist. The depression of fEPSPs induced by 5 microM CCh was reduced by either pirenzepine or M-105. (3) Furthermore, paired-pulse facilitation (PPF) was not affected by 0.1 microM CCh in control and Pb2+-exposed rats but was increased by 5 microM CCh in either group; the increase in PPF was less pronounced in Pb2+-treated when compared to control rats. These results suggested that cholinergic modulation could be impaired by Pb2+, and this kind of impairment might occur via different mAChR subtypes. Our study delineated the effects of Pb2+ on muscarinic modulation, and this might be one of the underlying mechanisms by which Pb2+ impairs learning and memory.

Monosialoanglioside (GM1) prevents lead-induced neurotoxicity on long-term potentiation, SOD activity, MDA levels, and intracellular calcium levels of hippocampus in rats.

Lead (Pb(2+)) is one of the most common neurotoxic metals present in our environment. Chronic or acute exposure to Pb(2+) causes impairment to the central nervous system (CNS). As one potent useful tool in the attempt to protect against impairment and promote functional recovery of the CNS, gangliosides are hopeful for recovering Pb(2+) neurotoxicity. The aim of this study is to investigate the effects of monosialoganglioside (GM1) on the Pb(2+)-induced impairments of synaptic plasticity, antioxidant system function, and intracellular calcium levels in the hippocampus of acute Pb(2+)-exposed rats. Our study showed that: (1) Acute Pb(2+) exposure impaired synaptic transmission and plasticity in the hippocampus and GM1 preconditioning rescued to some extent this impairment in urethane-anesthetized rats. (2) Superoxide dismutase activities and malondialdehyde levels were significantly increased in the acute Pb(2+)-exposed hippocampus which could be reduced by GM1 preconditioning. (3) Further, acute Pb(2+) exposure caused the internal free Ca(2+) fluctuation in the cultured hippocampal neurons and GM1 preconditioning could abate this fluctuation. Taken together, our results illustrated the possible mechanisms underlying the protective effects of GM1 against Pb(2+) neurotoxicity and might shed light on protection against Pb(2+) toxicity and its treatment.

Modulation of long-term potentiation by individual subtypes of muscarinic acetylcholine receptor in the rat dentate gyrus.

The roles of the muscarinic acetylcholine (ACh) receptors (mAChRs) in long-term potentiation (LTP) at many areas of the central nervous system including the hippocampus, have been extensively studied. However, not much is known about the modulation of LTP through individual subtypes of mAChR (M(1)-M(5) subtype). In this study, we investigated the involvement of each individual subtypes of mAChR in LTP induction by intrahippocampal administration of cholinergic ligands at the dentate gyrus (DG) of anesthetized rats. We found atropine, an antagonist of mAChRs, suppressed the induction of LTP. This observation confirmed that the muscarinic system is involved in LTP. We then examined the effects of M(1)AChR antagonists (pirenzepine and telenzepine), M(2/4)AChR antagonists (Methoctramine and {11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one}(AFDX-116)), and M(3/5)AChR antagonist (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP)) on LTP. Our results showed that both M(1)AChR and M(2/4)AChR antagonists but not M(3/5)AChR antagonist suppressed the amplitude of LTP. We also examined the effects of these cholinergic ligands on basal synaptic transmission and found that only pirenzepine augmented the amplitude of population spike. This study suggests that individual mAChR subtypes play different modulation roles in LTP induction in the DG of rats.

Effects of carbachol on lead-induced impairment of the long-term potentiation/depotentiation in rat dentate gyrus in vivo.

The present study aims at evaluating the impairment of LTP and depotentiation (DP) of LTP induced by acute lead exposure, and the effects of peripheral carbachol (CCh) application on LTP/DP of acute and chronic lead-exposed rats in dentate gyrus in vivo. Rats (80-100 days) were acutely exposed to lead by intraperitoneal injection of 0.2% lead acetate (PbAc) solution (1.5mg/100g) and/or CCh (1 micro g/100g). Rats were chronically exposed to lead from parturition through adulthood (80-100 days) by the drinking of 0.2% PbAc solution and/or CCh (1 micro g/100g) chronic intraperitoneal injection one week. The input-output (I/O) function, paired-pulse reaction (PPR), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in response to stimulation applied to the lateral perforant path. Results showed that: first, acute lead exposure significantly depressed the amplitudes of LTP/DP of both EPSP slope and PS amplitude. Second, CCh significantly increased the amplitudes of both EPSP LTP/DP and PS LTP of acute Pb-exposed rats. After CCh treatment, the magnitudes of EPSP LTP/DP and PS LTP of acute Pb-exposed rats showed no significant difference with controls. Third, Chronic CCh application also reversed chronic Pb-induced impairment of PS LTP and EPSP DP of LTP. As CCh does not cross blood-brain barrier in healthy animals, the data suggest that CCh may traverse BBB in Pb-exposed animals and cure Pb-induced dysfunction of learning and memory.

Effect of ganglioside on synaptic plasticity of hippocampus in lead-exposed rats in vivo.

Synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD) and depotentiation (DP), is important for learning and memory. Previous studies proved that chronic lead exposure especially during early post-natal development induced impairment on synapse plasticity. The purpose of this study is to evaluate the effect of ganglioside on the lead-induced impairments of LTP and DP in rat dentate gyrus in vivo. The experiments were carried out in three groups of rats (control, lead-exposed, ganglioside-treated lead-exposed, respectively). The input-output (I/O) function, pair pulses reaction, excitatory post-synaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (70-90 days) in response to stimulation applied to the lateral perforant path. The results show that (1) chronic lead exposure impaired LTP/DP measured on both EPSP slope and PS amplitude in DG area of the hippocampus. (2) The amplitudes of LTP/DP of lead-exposed group were significantly increased by supplying ganglioside. These results suggest intraperitoneally injection with ganglioside could reverse the lead-induced impairments of synaptic plasticity in rats and might be effective in attenuating the cognitive deficits induced by lead.

Age-related morphological impairments in the rat hippocampus following developmental lead exposure: an MRI, LM and EM study.

Lead is one of the most common neurotoxic metals present in our environment. Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Functional and morphological impairment of the rat brain has also been reported in the hippocampus (Hi) following developmental lead exposure. The present study was carried out to further investigate age-related morphological impairments in the rat Hi following developmental lead exposure with three methods: (1) magnetic resonance imaging (MRI); (2) light microscopy (LM); and (3) electron microscopy (EM) techniques. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking a 0.2% lead acetate solution. Age-related morphological alternations were investigated in the Hi of lead-exposed rats at various postnatal ages: postnatal day (PND) 17, 30 and 90. The MRI signal intensities (SIs) in the left, right, superior and inferior hippocampal regions of control and lead-exposed rats were analyzed. Compared with controls, the SIs of the four hippocampal regions of interest were significantly increased in lead-exposed rats at PND 17, 30 and 90. Moreover, the lead-induced impairment of the Hi showed an age-related decline and a specific topographical pattern. The impairment of inferior hippocampal regions was more severe than that of superior regions in lead-exposed rats at PND 17 and 30, while no significant difference of SIs was observed between left and right hippocampal regions in the three age groups, and between superior and inferior regions in the PND 90 lead-exposed rats. The LM observations indicated that the morphological injury of hippocampal neurons in lead-exposed rats was also age-related. The EM observations revealed that the endoplasmic reticular, Golgi complex and mitochondria of hippocampal CA1 and dentate gyrus neurons in lead-exposed rats were damaged. These results demonstrate that lead-induced morphological impairments of the rat Hi follow a specific age- and site-related pattern.