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ABSTRACT: Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long-term potentiation (LTP) but enhances long-term depression (LTD) induced by high- (HFS) and low-frequency stimulations (LFS), respectively. Using a pairing protocol under whole-cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age-matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V(ms)) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD-LTP crossover point of the voltage-response curve for synaptic plasticity. Prior repeated short-term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes- and activity-dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in Vms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.
European Journal of Neuroscience 08/2005; 22(1):169-78. · 3.63 Impact Factor
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D S Mathon,
H M B Lesscher,
M A F M Gerrits, A Kamal,
J E Pintar,
A G P Schuller,
B M Spruijt,
J P H Burbach,
M P Smidt,
J M van Ree,
G M J Ramakers
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ABSTRACT: There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement.
Neuroscience 02/2005; 130(2):359-67. · 3.38 Impact Factor
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ABSTRACT: The mossy fibers of the hippocampus display NMDA-receptor independent long-term plasticity. A number of studies addressed the role of mossy fiber long-term plasticity in memory, but have provided contrasting results. Here, we have exploited a genetic model, the rab3A null-mutant, which is characterized by the absence of both mossy fiber long-term potentiation and long-term depression. This mutant was backcrossed to 129S3/SvImJ and C57Bl/6J to obtain standardized genetic backgrounds. Spatial working memory, assessed in the eight-arm radial maze, was unchanged in rab3A null-mutants. Moreover, one-trial cued and contextual fear conditioning was normal. Long-term spatial memory was tested in the Morris water maze. Two different versions of this task were used, an 'easy' version and a 'difficult' one. On both versions, no differences in search time and quadrant preferences were observed. Thus, despite the elimination of mossy fiber long-term plasticity, these tests revealed no impairments in mnemonic capabilities. We conclude that spatial, contextual and working memory do not depend on mossy fiber plasticity.
Behavioural Brain Research 02/2003; 138(2):215-23. · 3.42 Impact Factor
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ABSTRACT: Diabetes mellitus is associated with impairments of cognitive function both in humans and animal models. In diabetic rats cognitive deficits are related to alterations in activity-dependent synaptic plasticity in the hippocampus. Many similarities with the pathophysiology of normal brain aging have been noted, and the view emerges that the effects of diabetes on the brain are best described as "accelerated brain aging."In the present study we examined whether CA1 pyramidal neurons from streptozotocin-induced diabetic rats display an increased slow afterhyperpolarization, often considered as a hallmark of neuronal aging. We found no differences in resting membrane potential, input resistance, membrane time-constant, and action potential amplitude and duration between CA1 pyramidal neurons from streptozotocin-induced diabetic and age-matched control rats. During a train of action potentials, however, there is an increased broadening of the action potentials in diabetic animals, so-called "spike broadening." The amplitude of the slow afterhyperpolarization elicited by a train of action potentials is indeed increased in diabetic animals. Interestingly, when the slow afterhyperpolarization is elicited by a Ca(2+) spike, there is no difference between control and diabetic rats. This indicates that the increased slow afterhyperpolarization in diabetes is likely to be due to an increased Ca(2+) influx resulting from the increased spike broadening. These data underscore the notion that the diabetic brain at the neuronal level shares properties with brain aging.
Neuroscience 02/2003; 118(2):577-83. · 3.38 Impact Factor
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ABSTRACT: In animal models of diabetes mellitus, such as the streptozotocin-diabetic rat (STZ-rat), spatial learning impairments develop in parallel with a reduced expression of long-term potentiation (LTP) and enhanced expression of long-term depression (LTD) in the hippocampus. This study examined the time course of the effects of STZ-diabetes and insulin treatment on the hippocampal post-synaptic glutamate N-methyl-D-aspartate (NMDA) receptor complex and other key proteins regulating hippocampal synaptic transmission in the post-synaptic density (PSD) fraction. In addition, the functional properties of the NMDA-receptor complex were examined. One month of STZ-diabetes did not affect the NMDA receptor complex. In contrast, 4 months after induction of diabetes NR2B subunit immunoreactivity, CaMKII and Tyr-dependent phosphorylation of the NR2A/B subunits of the NMDA receptor were reduced and alphaCaMKII autophosphorylation and its association to the NMDA receptor complex were impaired in STZ-rats compared with age-matched controls. Likewise, NMDA currents in hippocampal pyramidal neurones measured by intracellular recording were reduced in STZ-rats. Insulin treatment prevented the reduction in kinase activities, NR2B expression levels, CaMKII-NMDA receptor association and NMDA currents. These findings strengthen the hypothesis that altered post-synaptic glutamatergic transmission is related to deficits in learning and plasticity in this animal model.
Journal of Neurochemistry 03/2002; 80(3):438-47. · 4.06 Impact Factor
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Progress in brain research 02/2002; 138:305-14. · 3.04 Impact Factor
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ABSTRACT: In the present study, we investigated whether synaptic plasticity changes in the hippocampus of depressive-like socially stressed rats could be reversed by chronic antidepressant treatment. To that end, rats were either defeated and subsequently individually housed or subjected to control treatment followed by social housing. After a period of at least 3 months, rats were either treated chronically with imipramine (20 mg/kg per day, per os for at least 3 months) or the solvent solution (i.e. water). Then, long-term potentiation and depression were measured in the CA1 region of the hippocampus in vitro. Chronic imipramine treatment partially restored the attenuated induction of long-term potentiation and suppressed the facilitation of long-term depression-induction in socially stressed rats. The altered synaptic plasticity after social stress is discussed in relation to cognitive deficits and hippocampal changes that are observed in depressive patients.
Neuroscience Letters 09/2001; 309(3):153-6. · 2.11 Impact Factor
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ABSTRACT: NMDA receptor, Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII), and postsynaptic density 95 (PSD-95) are three major components of the PSD fraction. Both alphaCaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex. The nature and mechanisms of targeting to the NMDA receptor subunits are, however, not completely understood. Here we report that the C-terminal NR2A(S1389-V1464) sequence was sufficient to guarantee the association of both native and recombinant alphaCaMKII and PSD-95. PSD-95(54-256) was able to compete with the binding of both native and recombinant alphaCaMKII to the NR2A C-tail. Accordingly, alphaCaMKII(1-325) competes with both the native PSD-95 and the native kinase itself for the binding to NR2A. In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alphaCaMKII and PSD-95 to the NR2A C-tail. Finally, the association-dissociation of alphaCaMKII and PSD-95 to and from the NR2A C-tail was significantly modulated by activation of NMDA receptor achieved by either pharmacological tools or long-term potentiation induction, underlining the importance of dynamic and reciprocal interactions of NMDA receptor, alphaCaMKII, and PSD-95 in hippocampal synaptic plasticity.
Journal of Neuroscience 04/2001; 21(5):1501-9. · 7.11 Impact Factor
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ABSTRACT: Diabetes mellitus can lead to functional and structural deficits in both the peripheral and central nervous system. The pathogenesis of these deficits is multifactorial, probably involving, among others, microvascular dysfunction and oxidative stress. The present study examined the effects of 12 weeks of treatment with a conjugate of the essential fatty acid gamma-linolenic acid and the anti-oxidant alpha-lipoic acid (GLA-LA) on functional deficits in the peripheral and central nervous system in streptozotocin-diabetic rats. Treatment was initiated 16 weeks after diabetes induction. Sciatic nerve motor and sensory conduction velocity, brainstem auditory evoked potentials and visual evoked potentials were measured in control, untreated and GLA-LA treated diabetic rats. Also, long-term potentiation, a form of synaptic plasticity used as a model for learning and memory at the cellular level, was examined in hippocampal slices. GLA-LA treatment (50 mg/kg/day) did not reverse established deficits in nerve conduction velocity or in evoked potential latencies in diabetic rats. However, GLA-LA treatment did improve long-term potentiation in the hippocampus. It is concluded that GLA-LA, which is known to improve early deficits in peripheral nerve conduction in diabetic rats, is unable to reverse late deficits. However, the compound does reverse established deficits in long-term potentiation, suggesting that at least part of its activity is specifically directed at synaptic plasticity.
Journal of the Neurological Sciences 02/2001; 182(2):99-106. · 2.35 Impact Factor
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ABSTRACT: Diabetes mellitus leads to functional and structural changes in the brain which appear to be most pronounced in the elderly. Because the pathogenesis of brain ageing and that of diabetic complications show close analogies, it is hypothesized that the effects of diabetes and ageing on the brain interact. Our study examined the effects of diabetes and ageing on learning and hippocampal synaptic plasticity in rats.
Young adult (5 months) and aged (2 years) rats were examined after 8 weeks of streptozotocin-diabetes. Learning was tested in a Morris water maze. Synaptic plasticity was tested ex vivo, in hippocampal slices, in response to trains of stimuli of different frequency (0.05 to 100 Hz).
Statistically significant learning impairments were observed in young adult diabetic rats compared with controls. These impairments were even greater in aged diabetic animals. In hippocampal slices from young adult diabetic animals long-term potentiation induced by 100 Hz stimulation was impaired compared with controls (138 vs 218% of baseline). In contrast, long-term depression induced by 1 Hz stimulation was enhanced in slices from diabetic rats compared with controls (79 vs 92%). In non-diabetic aged rats synaptic responses were 149 and 93% of baseline in response to 100 and 1 Hz stimulation, compared with 106 and 75% in aged diabetic rats.
Both diabetes and ageing affect learning and hippocampal synaptic plasticity. The cumulative deficits in learning and synaptic plasticity in aged diabetic rats indicate that the effects of diabetes and ageing on the brain could interact.
Diabetologia 05/2000; 43(4):500-6. · 6.81 Impact Factor
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ABSTRACT: Within the hippocampal formation, two forms of long-lasting synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), can be induced which require the activation of NMDA receptors. Interestingly, it has been shown that both LTP and LTD are reduced in adult animals. Recently, a new chemical protocol has been described which elicits LTD in the CA1 field of the hippocampus. Application of 20 microM NMDA for 3 min results in a stable and long-lasting decrease in the evoked synaptic responses. We used this protocol to induce LTD in hippocampal slices from young and adult rats and show that this form of LTD is AP5-sensitive and can be blocked by the protein phosphatase inhibitor cyclosporin A in slices from adult animals. In contrast to electrical LTD (induced by prolonged low frequency stimulation), the extent of chemical LTD was not different between the young and adult rats. These findings indicate that the intracellular signal transduction cascades involved in long-lasting synaptic depression are still intact in adult animals.
European Journal of Neuroscience 11/1999; 11(10):3512-6. · 3.63 Impact Factor
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ABSTRACT: The effects of a low or high concentration of glucose in the perfusion medium on synaptic activity and plasticity were studied in hippocampal slices from rats. Low-glucose medium depressed the field excitatory post-synaptic potentials (fEPSP) significantly, whereas high-glucose medium had little effect on the fEPSP. Tetanization of the afferent fibres elicited significant potentiation (LTP) of synaptic activity irrespective of the glucose concentration in the medium. This may indicate that LTP induction does not depend on optimal neural transmission. Paired-pulse facilitation (PPF) experiments showed that the medium glucose concentration did not significantly influence potentiation of the second response.
Brain Research 05/1999; 824(2):238-42. · 2.73 Impact Factor
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ABSTRACT: Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. A progressive deficit was observed after a diabetes duration of six to eight weeks, which reached a maximum after 12 weeks of diabetes and remained stable thereafter. Next, long-term potentiation was examined in the dentate gyrus and in the CA3-field after 12 weeks of diabetes. Both were found to be impaired compared to controls. Finally, long-term depression was examined in the CA1-field of the hippocampus after 12 weeks of diabetes and found to be enhanced in slices from diabetic rats compared to controls. Changes in synaptic plasticity were observed in hippocampal slices from streptozotocin-diabetic rats. Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.
Neuroscience 04/1999; 90(3):737-45. · 3.38 Impact Factor
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ABSTRACT: Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.
Brain Research 08/1998; 800(1):125-35. · 2.73 Impact Factor
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ABSTRACT: Long-term depression, depotentiation and long-term potentiation of field excitatory postsynaptic potentials in the CA1 field of the hippocampus were studied in slices from two-, 12-, 24- and 36-week-old rats. Long-term potentiation was induced by stimulating afferent fibres for 1 s at 100 Hz. Long-term depression was induced either by stimulating the afferent pathways twice for 15 min at 1 Hz (protocol 1), giving in total 1800 pulses, or by stimulating the fibres at 5 min intervals twice at 1 Hz for 5 min followed by 5 min stimulation at 5 Hz (protocol 2), giving in total 2100 pulses. We found significant long-term depression in slices of all groups stimulated with protocol 1; however, the magnitude of long-term depression in slices from 24- and 36-week-old rats was significantly lower than that in slices from two- and 12-week old rats, although there was no such difference in the magnitude of long-term potentiation between slices. Stimulation protocol 2 induced long-term depression only in slices from two- and 12-week-old rats. Comparison of the dynamic range of transmission plasticity in slices from two- and 36-week-old rats, calculated as the difference between the nearly saturated long-term potentiation and nearly saturated depotentiation, revealed a significantly smaller dynamic range in slices from 36-week-old rats in comparison with slices from two-week-old animals. The decrease in the dynamic range in slices from 36-week-old rats was due to a diminished capacity to depotentiate the nearly saturated long-term potentiation and not due to a decreased long-term potentiation expression in these slices. In contrast to long-term depression, in which the slope of the field excitatory postsynaptic potentials consistently and significantly decreased below the baseline level, the nearly saturated depotentiation did not decrease below the original, pre-long potentiation baseline level. The results demonstrate that increasing age reduces expression of long-term depression and the dynamic range of transmission plasticity.
Neuroscience 05/1998; 83(3):707-15. · 3.38 Impact Factor
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ABSTRACT: Moderate impairment of learning and memory has been recognized as a complication of diabetes. The present study examined behavioral and electrophysiological measures of cerebral function in streptozotocin (STZ)-induced diabetic rats. Behavioral testing consisted of a spatial learning task in a water maze. Electrophysiological testing consisted of in vitro assessment of hippocampal long-term potentiation (LTP), an activity-dependent form of synaptic plasticity, which is believed to be related to the cellular mechanisms of learning and memory. Two experiments were performed: the first with severely hyperglycemic rats and the second with moderately hyperglycemic rats. Rats were tested in the water maze 11 weeks after induction of diabetes. Next, LTP was measured in vitro in trained animals. Both spatial learning and LTP expression in the CA1 field of the hippocampus were impaired in severely hyperglycemic rats as compared with nondiabetic controls. In contrast, spatial learning and hippocampal LTP were unaffected in moderately hyperglycemic rats. The association of alterations in hippocampal LTP with specific learning impairments has previously been reported in conditions other than diabetes. Our findings suggest that changes in LTP-like forms of synaptic plasticity in the hippocampus, and possibly in other cerebral structures, are involved in learning deficits in STZ-induced diabetes. The beneficial effect of moderate glycemic control on both place learning and hippocampal LTP supports the significance of the relation between these two parameters and indicates that the development of the observed deficits may be related to the level of glycemic control.
Diabetes 10/1996; 45(9):1259-66. · 8.29 Impact Factor
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ABSTRACT: Diabetes mellitus is associated with impairments of cognitive function both in humans and animal models. In diabetic rats cognitive deficits are related to alterations in activity-dependent synaptic plasticity in the hippocampus. Many similarities with the pathophysiology of normal brain aging have been noted, and the view emerges that the effects of diabetes on the brain are best described as 'accelerated brain aging.' In the present study we examined whether CA1 pyramidal neurons from streptozotocin-induced diabetic rats display an increased slow afterhyperpolarization, often considered as a hallmark of neuronal aging. We found no differences in resting membrane potential, input resistance, membrane time-constant, and action potential amplitude and duration between CA1 pyramidal neurons from streptozotocin-induced diabetic and age-matched control rats. During a train of action potentials, however, there is an increased broadening of the action potentials in diabetic animals, so-called 'spike broadening.' The amplitude of the slow afterhyperpolarization elicited by a train of action potentials is indeed increased in diabetic animals. Interestingly, when the slow afterhyperpolarization is elicited by a Ca2+ spike, there is no difference between control and diabetic rats. This indicates that the increased slow afterhyperpolarization in diabetes is likely to be due to an increased Ca2+ influx resulting from the increased spike broadening. These data underscore the notion that the diabetic brain at the neuronal level shares properties with brain aging.
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ABSTRACT: Synaptically released glutamate binds to ionotropic or metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and can be divided into three subclasses (Group IIII) depending on their pharmacology and coupling to signal transduction cascades. Group I mGluRs are coupled to phospholipase C and are implicated in several important physiological processes, including activity-dependent synaptic plasticity, but their exact role in synaptic plasticity remains unclear. Synaptic plasticity can manifest itself as an increase or decrease of synaptic efficacy, referred to as long-term potentiation (LTP) and long-term depression (LTD). The likelihood, degree and direction of the change in synaptic efficacy depends on the history of the synapse and is referred to as 'metaplasticity'. We provide direct experimental evidence for an involvement of group I mGluRs in metaplasticity in CA1 hippocampal synapses. Bath application of a low concentration of the specific group I agonist 3,5-dihydroxyphenylglycine (DHPG), which does not affect basal synaptic transmission, resulted in a leftward shift of the frequencyresponse function for the induction of LTD and LTP in naïve synapses. DHPG resulted in the induction of LTP at frequencies which induced LTD in control slices. These alterations in the induction of LTD and LTP resemble the metaplastic changes observed in previously depressed synapses. In addition, in the presence of DHPG additional potentiation could be induced after LTP had apparently been saturated. These findings provide strong evidence for an involvement of group I mGluRs in the regulation of metaplasticity in the CA1 field of the hippocampus.
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ABSTRACT: The aim of this study was to investigate long-term effects of neonatal treatment with the synthetic glucocorticoid (GC) hormone dexamethasone (DEX) on hippocampus functions in the rat. The questions we asked were 1) Does neonatal treatment with DEX lead to impaired hippocampus-dependent spatial learning later in life? 2) If so, is this impairment associated with a deficit in hippocampal synaptic plasticity, a putative neuronal substrate of learning? and 3) Does neonatal DEX treatment affect the postsynaptic hippocampal NMDA receptor complex, known to be critically involved in spatial learning and synaptic plasticity?
