Hippocampus
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This speculative review serves two purposes. First, it as an extension of the ideas we developed in a previous review (Diamond et al., Hippocampus, 2004;14:281-291), and second, it is a rebuttal to Abraham's (Hippocampus, 2004;14:675-676) critique of that review. We had speculated on the functional significance of the finding that post-training LTP induction produces retrograde amnesia. ⋯ Here, within the context of a reply to Abraham's critique, we have provided a review of the literature on the influence of stress, novelty, fear conditioning, and the retrieval of emotional memories on cognitive and physiological measures of hippocampal functioning. An emphasis of this review is our hypothesis that endogenous forms of depotentiation, LTD and LTP are generated only when arousing experiences occur in conjunction with memory-related activation of the hippocampus and amygdala. We conclude with speculation that interactions among the different forms of endogenous plasticity underlie a form of competition by synapses and memories for access to retrieval resources.
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DNA repair plays a critical, but imprecisely defined role in excitotoxic injury and neuronal survival throughout adulthood. We utilized an excitotoxic injury model to compare the location and phenotype of degenerating neurons in mice (strain 129-C57BL) deficient in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), an enzyme required for nonhomologous end joining (NHEJ). Brains from untreated adult heterozygous and DNA-PKcs null mice displayed comparable cytoarchitecture and undetectable levels of cell death. ⋯ Addition of pifithrin-alpha, a p53 inhibitor, or expression of a dominant-negative p53 rescued neurons from kainate-induced excitotoxic cell death in primary cortical cultures derived from wildtype, DNA-PKcs heterozygous, or DNA-PKcs null neonatal mice. Moreover, pifithrin-alpha prevented kainate-induced loss of mitochondrial membrane potential, dendrite degeneration, and cell death. Results suggest that NHEJ plays a neuroprotective role in excitotoxicity, within the perforant, Schaffer collateral, hippocampal-septal, and temperoammonic pathways, in part by repairing DNA damage that would otherwise result in activation of a p53-dependent apoptotic cascade.
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In examining the role of Class 3 secreted semaphorins in the prenatal and postnatal development of the septohippocampal pathway, we found that embryonic (E14-E16) septal axons were repelled by the cingulate cortex and the striatum. We also found that the hippocampus exerts chemorepulsion on dorsolateral septal fibers, but not on fibers arising in the medial septum/diagonal band complex, which is the source of septohippocampal axons. These data indicate that endogenous chemorepellents prevent the growth of septal axons in nonappropriate brain areas and direct septohippocampal fibers to the target hippocampus. ⋯ In contrast, cholinergic septohippocampal fibers terminated onto sema 3E and sema 3A-expressing pyramidal and granule cells. The data suggest that Class 3 secreted semaphorins are involved in postnatal development. Moreover, because GABAergic and cholinergic axons terminate onto neurons expressing distinct, but overlapping, patterns of semaphorin expression, semaphorin functions may be regulated by different signaling mechanisms at postnatal stages.
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Repeated vivid recalls or flashbacks of traumatic memories and memory deficits are the cardinal features of post-traumatic stress disorder (PTSD). The underlying mechanisms are not fully understood yet. Here, we examined the effects of very strong fear conditioning (20 pairings of a light with a 1.5-mA, 0.5-s foot shock) and subsequent reexposure to the conditioning context (chamber A), a similar context (chamber B), and/or to the fear conditioned stimulus (CS) (a light) on synaptic plasticity in the hippocampal CA1 area in anesthetized Sprague-Dawley rats. ⋯ The induction of long-term depression (LTD) was facilitated immediately, but not 24 h, after fear conditioning. Only reexposure to the CS in the CA, but not reexposure to either chamber A or B alone, or the CS in chamber B, 24 h after conditioning, reinstated the facilitation of LTD induction. These data demonstrate that unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm can have profound effects on hippocampal synaptic plasticity, which may aid to understand the mechanisms underlying impairments of hippocampus-dependent memory by stress or in PTSD.
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The induction threshold, and the magnitude and direction of changes in synaptic plasticity may depend on the previous history of neuronal activity. This phenomenon, termed "metaplasticity," could play an important role in integration processes by coordinating the modulation of synapses. Although metaplasticity has been analyzed extensively, its underlying cellular mechanisms remain largely unknown. ⋯ This reduction in excitability temporarily prevented nonpotentiated synaptic inputs to exhibit an LTP induced by presynaptic tetanization. This metaplasticity was strongly resistant to increases in the magnitude of synaptic tetanization protocols. We propose that this heterosynaptic metaplasticity, mediated by intrinsic cellular mechanisms, triggered by brief periods of activity, and relying on changes of a slow Ca2+-activated K+ current, may contribute to adjusting the efficacy of synaptic connections and shaping network behavior to regulate integration processes.