Discussion

The neurobehavioral deficits following postnatal lead exposure involve primarily an inability to consolidate memory into long-term storage as described previously.32 Recall of the aversive stimulus in control animals was robust and avoidance latency did not decline significantly for 5 days. In contrast, recall latency declined significantly by posttraining day 5 in animals postnatally exposed to lead; this effect is specific to the learned response, as no obvious behavioral alterations were observed in open-field studies. Recall was unaffected in lead exposed animals within 48 h posttraining, indicating that the task was acquired successfully but was not processed effectively. This is consistent with impaired modulation of NCAM polysialylation observed in the 10-12 h posttraining period of consolidation. Moreover, the basal frequency of dentate polysialylated neurons was unaffected in the lead exposed groups prior to and following learning-induced modulations of NCAM PSA; this suggests that developmental exposure to inorganic lead results in an enduring inability to fully activate the polysia-lylation response by mechanisms largely independent of the regulatory polysialyltransferase.

These observations raise a number of issues with respect to the long-term consequences of postnatal lead exposure. It is likely that this study identifies the minimal effects of postnatal exposure to inorganic lead, because the exposure was restricted to the final stages of synapse elaboration. In contrast, perinatal exposure results in enduring cell loss and more severe learning deficits, including impaired acquisition.3234 Nevertheless, the exposure protocol was sufficient to induce a significant hippocampal CA1 synaptic deficit in the order of 40%.27 The same reduction in posttraining poly-sialylation response was observed in animals with lead exposure; thus, it is tempting to speculate that this reduction reflects enduring deficits in synaptic complement and inability to mount a neuroplastic response of appropriate magnitude during memory consolidation. This is speculative because there are no systematic studies on the long-term consequences of postnatal lead exposure on synaptic complement in all regions of hippocampal formation. However, it is consistent with the fact that synapse formation is required during memory consolidation in the hippocampal dentate gyrus and the CA1 region.151637 Similarly, impaired synaptic growth has been associated with reduced persistence of LTP in the dentate gyrus of conscious rats exposed developmentally to inorganic lead.38

In this study, a temporal delay is observed in the learning-associated polysialylation response that suggests a defect in associated activation mechanisms. Although memory may be committed to the processes of long-term storage it remains malleable to extrinsic transmitter influences up to at least 12 h posttraining. For example, cholinergic antagonism 6-8 h posttraining and D1-mediated dopamine agonism 10-12 h posttraining cause loss of learning-associated NCAM polysialylation activation and amnesia at 24 h posttraining.39 Lead-induced delay in learning-associated polysialylation may be relevant to the dopamine receptor supersensitivity observed in animals postnatally exposed to lead.4,40

These lead-induced learning deficits emerge after a lengthy delay; however; this is not at variance with the period of hippocampal function in memory consolidation. Primate and rodent lesion studies demonstrate that it requires several days for consolidation of associative tasks within the hippocampus.4142 Thus, irrespective of the mechanism of action, the minimal long-term consequence of neurodevelopmental lead exposure appears to be an enduring deficit in hippocampal memory consolidation. This view is supported by the inherent ability of the basal forebrain cholinergic system to recover from lead exposure and the belief that this system subserves more general regulatory aspects of cognition rather than specific mnemonic functions.34 43

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