Occlusion of low-frequency-induced, heterosynaptic long-term potentiation in the rat hippocampus in vivo following spatial training.

Recent work has shown that some low-frequency stimulation (LFS) protocols can induce long-term potentiation (LTP) at hippocampal synapses. As LFS mimics certain aspects of low-frequency oscillations during slow-wave sleep, LFS-LTP may be relevant to processes of sleep-dependent consolidation. Here, alternating LFS (1 Hz) of heterosynaptic inputs arising in the medial septum and area CA3 induced LTP at hippocampal CA1 synapses of anesthetized rats. Remarkably, this LTP was absent when delivered 3 h, but not 8 or 24 h, after training in the hidden platform version of the Morris water maze, suggesting a time-specific occlusion of LFS-LTP following spatial learning. LTP assessed 3 h after training was intact in yoked swim controls and rats trained in darkness. Visible platform training resulted in heterogeneous effects, with about half of the animals showing LTP occlusion. Pharmacological experiments revealed that N-methyl-d-aspartate (NMDA)-receptor activation was required for both LFS-LTP and the retention of spatial learning. To test whether a learning-related, NMDA-dependent potentiation accounted for the occlusion effect, we blocked NMDA receptors immediately following spatial training. This manipulation reversed LTP occlusion 3 h after training. Together, these experiments indicate a mechanistic overlap between heterosynaptically induced LFS-LTP and processes mediating the consolidation of spatial information at hippocampal synapses.

Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain.

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)-α, 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-α 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-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. 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-ß phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-ß peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD.

Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation.

Subchronic NMDA receptor antagonist treatment and post-weaning social isolation are two animal models of schizophrenia symptoms. However, behavioral and physiological changes following a combination of these two procedures have not been investigated. Thus, we examined effects of a novel, "double hit" model combining these two treatments, comparing them to standard models involving only NMDA antagonist treatment or social isolation. Male, Sprague-Dawley rats were either group-housed or maintained in social isolation (starting at postnatal day [PD] 21 and continuing throughout the study). Each housing condition was further subdivided into two groups, receiving either subchronic treatment with either saline or MK-801 (0.5mg/kg, i.p., 2xday for seven days starting at PD 56). Post-weaning social isolation increased locomotor activity (assessed at PD 70) in response to a novel environment and an acute amphetamine injection, while subchronic MK-801 increased only amphetamine induced locomotor activity. Subsequent electrophysiological experiments (under urethane anesthesia) assessing changes in plasticity of hippocampal synapses showed that subchronic MK-801 treatment resulted in an increase in long-term potentiation in area CA1 in response to high frequency stimulation of the contralateral CA3 area, while housing condition had no effect. No other changes in hippocampal electrophysiology (input-output curves, paired-pulse facilitation) were observed. These data are the first to demonstrate an enhancement in hippocampal long-term plasticity in vivo following subchronic MK-801 administration, an effect that may be related to the well-characterized changes in glutamatergic and GABAergic systems seen after subchronic NMDA receptor blockade. That lack of additive or synergistic effects in the "double hit model" suggests that combining isolation and subchronic MK-801 treatment does not necessarily produce greater behavioral or physiological dysfunction than that seen with either treatment alone.

Low-frequency-induced synaptic potentiation: a paradigm shift in the field of memory-related plasticity mechanisms?

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.

Alternating low frequency stimulation of medial septal and commissural fibers induces NMDA-dependent, long-lasting potentiation of hippocampal synapses in urethane-anesthetized rats.

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.

Predator (cat hair)-induced enhancement of hippocampal long-term potentiation in rats: involvement of acetylcholine.

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.