Persistent changes in learning and memory in rats following neonatal treatment with domoic acid (original) (raw)
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Neurotoxicity Research, 2004
It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 µg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 µg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid.In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.
The purpose of the present study was to determine whether early alterations in glutamate signaling, via daily injections of the glutamate agonist, domoic acid (DOM; 20 μg/kg), during a critical period of CNS development , would result in temporal memory deficits and/or alterations in tyrosine hydroxylase (TH) immunoreactivity. As adults, subjects were assessed for temporal memory ability using a recency discrimination paradigm. Both number and duration of exploratory contacts directed at familiar objects, differing by one hour in recall delay, were measured. Analyses revealed that DOM-treated females demonstrated temporal memory dysfunction, as evidenced in a significantly lower proportion of total exploratory behaviour directed toward the remote object. Integrity of the dopamine system was assessed using immunohistochemistry to examine TH immunoreactivity in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Sections obtained from DOM-treated males had significantly less TH immunoreactivity in the right mPFC, while DOM-treated females had significantly greater TH immunoreactivity in the left core and right shell of the NAcc. These findings are discussed in context of early alterations to glutamate signaling in the development of human neuropsychiatric disorders.
Parenteral domoic acid impairs spatial learning in mice
Pharmacology, Biochemistry and Behavior, 1992
The present study is the first to examine the effect of a single intraperitoneal injection of the neuroexcitotoxin domoic acid on learning in mice. Compared to saline controls, animals exposed to domoic acid (2.0 mg/kg) showed significant impairment on the acquisition of the place task in the Morris water maze. Observation of swim paths taken by mice searching for the underwater platform revealed a failure on the part of the domoic acid-exposed mice to select the appropriate problem solving strategies. The results, along with neuroanatomic work done here and elsewhere, suggest that impairment of acquisition and retention of this spatial navigation task by domoic acid, involves a neuropathology that includes not only the hippocampus, but other limbic, and possibly extralimbic brain regions. Domoic acid Acquisition Spatial navigation Learning Hippocampus Morris water maze Neuroexcitant amino acid Neurotoxin Neuroexcitotoxin Mouse Place task Mussel toxin
Low doses of non-NMDA glutamate receptor agonists alter neurobehavioural development in the rat
Neurotoxicology and Teratology, 2003
While it is known that glutamate is critical to CNS development and function, less is known about the role of kainate receptors, a subclass of ionotropic glutamate receptors, during ontogeny. This is especially true with respect to the emergence and expression of behaviour. It is also known that the neonatal CNS differs from that of adults with respect to excitatory amino acid (EAA) toxicity. Our aim was to determine the effects of early low-dose stimulation of kainate receptors on physical and behavioural development in the rat. Saline, one of two subtoxic doses of domoic acid (DOM) (5 and 20 μg/kg), or in a parallel study, saline, or one of two pharmacologically equivalent doses of kainic acid (KA) (25 and 100 μg/kg), were systemically administered once daily from postnatal days (PNDs) 8–14. While DOM or KA had no effect on typical measures of toxicity such as weight gain, acoustic startle, ultrasonic vocalizations (UVs), or maternal retrieval, these doses were shown to be physiologically relevant, producing particular group differences in eye opening, conditioned place preference, and activity levels. We conclude that administration of very low doses of selective kainate receptor agonists during the second postnatal week produces changes in neurobehavioural development in the rat.
Brain Research, 1994
The relationship between hippocampal damage and spatial learning deficiencies was studied in rats injected with kainic acid (10 mg/kg i.p.). A single injection was given either before or after the acquisition phase of the Morris water-maze task. In this acquisition phase, the animals were required to find a hidden underwater platform starting from four different points. The task was repeated twice a day for 10 days. In the retention phase after 10 days rest, the rats repeated the same task. The damage caused by the treatment occurred in several prosencephalic areas, including the piriform and enthorhinal cortices, the thalamus and the hippocampus. In the latter, greatest damage was seen in CA1 followed by CA3 while CA2 and the gyrus dentatus appeared almost unaffected. The behavioural results indicated that kainic acid impaired but did not preclude the acquisition of the water-maze task. During the retention phase, no significant differences in latencies were found between animals that were treated before and after acquisition, thus, indicating that pretraining does not play an important role in the recovery of these spatial abilities following hippocampal lesions.
NMDA receptor involvement in the effects of low dose domoic acid in neonatal rats
Amino Acids, 2005
We have previously reported that neonatal rats display enhanced sensitivity to domoic acid relative to adults, and that perinatal injections of low doses of domoic acid alter early associational learning in the newborn rat. The current study was designed to further investigate the effects of low dose domoic acid on neonatal odour conditioning and to determine if the observed effects are due in part to an action on NMDA receptors. Groups of rat pups were conditioned to a novel odour on postnatal day (PND) 8, injected with 20 μg/kg domoic acid either alone, or in combination with the NMDA antagonist CPP (or appropriate controls), daily from day 8–14, reexposed to the conditioning odour or a novel odour on day 9, and tested for odour preference on day 13 using a standard 3-choice paradigm. Results indicated that rats treated with domoic acid spent significantly more time over the conditioning odour than did saline-treated rats when tested on PND 13. This effect was antagonized by concomitant injection of CPP, indicating an involvement of NMDA receptors in the actions of DOM in this paradigm. Rats injected with either saline or CPP alone showed the opposite effect, i.e. a preference for the alternate odour. The results indicate that a very low dose of DOM produces a conditioned odour preference in neonatal rats and that this effect is due in part to NMDA receptor involvement, thereby emphasizing a role for both kainate and NMDA glutamate receptors in implicit memory.
Neonatal exposure to monosodium glutamate disrupts place learning ability in adult rats
Pharmacology Biochemistry and Behavior, 2005
The activation of glutamatergic NMDA receptors of the hippocampus is closely associated with expression of place learning. Neonatal exposure to monosodium glutamate leads to abnormal expression of NMDA receptor subunits in the hippocampus, but its effect on place learning is unknown. Place learning acquisition and retrieval were assessed in mature adult rats after subcutaneous injection of monosodium glutamate (4 mg/g body weight) in eight neonatal rat pups at postnatal days one, three, five, and seven. Eight untreated rats were used as controls. At four months of age, the rats were challenged over a period of nine days with a place learning task. The task used an acquisition-retrieval paradigm in a Morris maze. Place learning acquisition was impaired in the experimental rats, which were unable to reduce their escape latencies during the nine training days. Controls improved between the fifth and ninth days of training. Test trials showed that retrieval of spatial information was also impaired in the experimental animals. These results show that both place learning acquisition and retrieval abilities in mature rats are impaired by neonatal treatment with monosodium glutamate. These findings may be related to the abnormal expression of NMDA receptor subunits in the hippocampus.
Glutamate, learning and dementia-selection of evidence
Amino Acids, 1994
Initial suggestions on the involvement of glutamate in memory came from electrophysiological studies on LTP that is blocked by NMDAantagonists. Then Morris and colleagues (1986) provided the first evidence that icy infusion of the competitive NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) to rats, inhibits both LTP in vivo and spatial learning in a Morris water maze. This was followed by a great amount of evidence confirming the initial finding in various learning tasks. The present paper is devoted to critical review of the literature focusing on the following problems: which glutamate receptors are involved ?, in which tests NMDA antagonists inhibit learning ?; which types of memory are affected ?; which brain structures are involved ?; do NMDA receptor antagonists invariably impair learning ?; is the effect of NMDA receptors antagonists on learning specific ?; does the stimulation of NMDA receptors result in cognitive enhancement ?. Effects of MK-801 on learning and memory as assessed using a novel water maze. Soc Neurosci Abst 16:767 Keith JR, Rudy JW (1990) Why NMDA-receptor-dependent long-term potentiation may not be a learning and memory mechanism. Or is it memorex? A reply to Morris, Gallagher, and Staubli. Psychobiology 18:269-272 Keller EA, Borghese CM, Carrer HF, Ramirez OA (1992) The learning capacity of high or low performance rats is related to the hippocampus NMDA receptors. Brain Res 576: 162-164 Kesner RP, Dakis M (1993) Phencyclidine disrupts acquisition and retention performance within a spatial continuous recognition memory task. Pharmacol Biochem Behav 44: 419-424 Kesner RP, Dakis M, Boltand BL (1993) Phencyclidine disrupts long-term but not shortterm memory within a spatial learning task. Psychopharmacology 111:85-90 Kim M, Mcgaugh JL (1992) Effects of intra-amygdala injections of NMDA receptor antagonists on acquisition and retention of inhibitory avoidance. Brain Res 585:35-48 Kim J J, Landeira-Fernandez J, DeCola JP, Fenselow MS (1990) NMDA receptors mediate acquisition but not expression of pavlovian fear conditioning. Soc Neurosci Abst 16:768 Kitamura Y, Zhao XH, Ohnuki T, Takei M, Nomura Y (1992) Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse. Neurosci Lett 137:169-172 Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA receptors expressed in Xenopus oocytes. Science 214:835-837 Koek W, Woods JH, Ornstein P (1987) A simple and rapid method for assesing similarities among directly observable behavioral effects of drugs: PCP-like effect of 2-amino-5phosphonovalerate in rats. Psychopharmacology 91:297-304 Kuraishi Y, Ueda M, Fujji T, Satoh M (1991) Bifemelane enhances glutamate release from mossy fiber synaptosome of guinea-pig hippocampus: involvement of protein kinase C. Soc Neurosci Abstr 17:578 Lalonde R, Cote C (1993) Behavioral effects of non-NMDA glutamate receptor antagonists. Neurosci Biobehav Rev 17:79-84
Aging of glutamate receptors: correlations between binding and spatial memory performance in mice
Mechanisms of Ageing and Development, 1998
C57Bl/6 mice aged 3, 10, and 26 months were tested for spatial learning in the Morris water maze. Ten and 26 month old mice were ad libitum-fed or diet restricted (60% of ad libitum-fed calories). Diet restriction significantly improved memory performance among the 10 and 26 month olds. In age/diet group comparisons, aged ad libitum-fed mice had significantly higher average proximity scores, indicating poorer performance, in probe trials for place learning than the 3 month olds and diet restricted 10 month olds. Diet restricted 26 month olds did not differ significantly from 3 month olds or any other groups in probe trial measures. The group means for average proximity scores were significantly correlated with binding densities for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the frontal cortex and CA1 region of the hippocampus. h-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) binding correlated with group proximity scores in frontal and parietal cortices and within the CA1 and CA3 regions of the hippocampus. Kainate and metabotropic binding sites showed no significant correlations with behavior. These results suggest that there is a sparing of spatial memory with diet restriction in aging C57Bl/6 mice and that the effects of aging on NMDA and AMPA receptors may be associated with age-related declines in spatial learning.