Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-␣, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-␣ is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-␣ signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-␣ receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-␣ receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-␣. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-␤ phagocytic marker expression and phagocytosis activity, indicating that intact TNF-␣ receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-␤ peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-␣ inhibitors for the treatment of

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Recent evidence indicates that some synapses exhibit long-lasting synaptic potentiation in response to low frequency (1 Hz) stimulation, similar to long-term potentiation (LTP) following high frequency induction protocols. Here, the authors characterize a form of long-lasting synaptic potentiation in the hippocampal CA1 area following alternating, single pulse stimulation of the medial septum (MS) and hippocampal CA3 commissural fibers (MS-H LTP). In urethane-anesthetized rats, alternating single pulse stimulation of the MS and CA3 (50 pulses each at 0.5 Hz, 1,000 ms interstimulus interval [ISI]) produced gradual increases of field excitatory postsynaptic potential (fEPSP) amplitude in CA1 ( approximately 123% of baseline), while MS or CA3 stimulation alone was ineffective. The fEPSP enhancement was long-lasting (>4h) and repeated episodes of alternating MS-CA3 stimulation tended to result in greater levels of potentiation than those elicited by a single episode. Surprisingly, ISIs of 500, 750, and 1,500 ms did not result in significant changes in fEPSP amplitude, while an ISI of 100 ms produced synaptic depression. MS-H LTP was resistant to systemic administration of nicotinic and muscarinic receptor antagonists (scopolamine, mecamylamine), but abolished by systemic MK-801 (0.5 mg/kg, i.p.) or local CA1 application of AP-V (10 mM), indicative of a critical role of hippocampal NMDA receptors in this effect. Paired-pulse facilitation experiments revealed a gradually developing, significant inverse correlation between fEPSP enhancement and decrease in paired-pulse facilitation ratio, suggesting a role of changes in presynaptic transmitter release. Together, these data demonstrate a novel form of long-lasting synaptic enhancement in CA1 neurons in response to low frequency activity in separate afferent systems, an activity that might mimic some aspects of natural discharge patterns during the acquisition or consolidation of memory processes in hippocampal circuits.

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity thought to play functional roles in learning and memory processes. It is generally assumed that the direction of synaptic modifications (i.e., up- or down-regulation of synaptic strength) depends on the specific pattern of afferent inputs, with high frequency activity or stimulation effectively inducing LTP, while low-frequency patterns often elicit LTD. This dogma ("high frequency-LTP, low frequency-LTD") has recently been challenged by evidence demonstrating low frequency stimulation (LFS)-induced synaptic potentiation in the rodent hippocampus and amygdala. Extensive work in the past decades has focused on deciphering the mechanisms by which high frequency stimulation of afferent fiber systems results in LTP. With this review, we will compare and contrast the well-known synaptic and cellular mechanisms underlying classical, high-frequency-induced LTP to those mediating the more recently discovered phenomena of LFS-induced synaptic enhancement. In addition, we argue that LFS protocols provide a means to more accurately mimic some endogenous, oscillatory activity patterns present in hippocampal and extra-hippocampal (especially neocortical) circuits during periods of memory consolidation. Consequently, LFS-induced synaptic potentiation offers a novel and important avenue to investigate cellular and systems-level mechanisms mediating the encoding, consolidation, and transfer of information throughout multiple forebrain networks implicated in learning and memory processes. (c) 2009 Wiley-Liss, Inc.

Extensive literature has demonstrated that arousal and fear modify memory acquisition and consolidation. Predator hair and odors increase arousal in rats and, therefore, may influence information encoding and synaptic plasticity in the rodent nervous system. In behavioral experiments, we confirm that laboratory-bred Long Evans rats avoid cat hair. Electrophysiological work in vivo showed that long-term potentiation (LTP) in the dentate gyrus induced by perforant path stimulation was enhanced for 5-7 days when LTP induction occurred in the presence of cat hair relative to fake hair. The muscarinic receptor antagonist scopolamine (i.p.) reversed the cat hair-elicited LTP enhancement without affecting weaker LTP elicited in the presence of fake hair. Thus, exposure to a predator stimulus elicits a cholinergically-dependent state of heightened plasticity that may serve to facilitate information storage in hippocampal circuits.Memory formation is a dynamic and selective process, and the attentional selection and subsequent encoding of stimuli in memory systems are influenced by emotional arousal and stress (e.g., McGaugh 2000McGaugh , 2004Vuilleumier 2005;LeBar and Cabeza 2006). In several species, including humans, acute increases in arousal and related adrenal hormones can enhance the consolidation of stimuli experienced in close temporal proximity to the hormonal activation, leading to stronger encoding of emotionally arousing material relative to more neutral stimuli (Cahill et al. , 2000McGaugh 2000;McGaugh and Roozendaal 2002).Extensive evidence suggests that the effect of arousal to facilitate memory consolidation is mediated by the basolateral amygdala. Local, intra-amygdala application of arousal-related pharmacological agents (e.g., adrenergic, noradrenergic, or glucocorticoid agonists) can enhance memory consolidation, while lesions of the basolateral amygdala block arousal-induced memory modulation (Packard et al. 1994;Cahill and McGaugh 1998;McGaugh 2004). Further, the amygdala also influences synaptic plasticity in several forebrain systems, with electrical activation of amygdala neurons enhancing long-term potentiation (LTP) at hippocampal, thalamocortical, and corticostriatal synapses (Akirav and Richter-Levin 1999;Frey et al. 2001;Dringenberg et al. 2004;Popescu et al. 2007). Thus, the basolateral amygdala serves as a critical interface linking arousal states, plasticity mechanisms, and memory consolidation (Cahill and McGaugh 1998;Paré 2003;McGaugh 2004;LeBar and Cabeza 2006).Here, we tested whether an innately arousing and aversive stimulus, cat hair (Dielenberg and McGregor 2001;Apfelbach et al. 2005), is effective in modulating hippocampal LTP in rats under in vivo conditions. Further, given the role of acetylcholine (ACh) in mediating arousal-and amygdala-induced memory consolidation and plasticity (Frey et al. 2001;Dringenberg et al. 2004;McGaugh 2004) All experimental procedures were conducted in accordance with the guidelines of the Canadian Council on Animal Care and approved by the Queen's...