Paul F. Chapman

Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Aβ(1–40) and a 14-fold increase in Aβ(1–42/43) accompanied the appearance of these behavioral deficits. Numerous Aβ plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Aβ. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimers disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimers disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimers patients.

The role of nitric oxide in hippocampal long-term potentiation

Long-term potentiation is a long-lasting, use-dependent increase in the strength of synaptic connections. We investigated the role of nitric oxide (NO) in determining the duration of potentiation induced by high frequency stimulation of afferents in the CA1 region of the rat hippocampus. The calcium/calmodulin-dependent production of NO can be initiated by activation of excitatory amino acid receptors and results in increased levels of cGMP in target cells. Here we report that only a relatively short-term potentiation can be induced in the presence of nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor. The effects of L-NAME on the duration of potentiation are partially reversed by coadministration of L-arginine, a precursor of neuronal NO, and by dibutyryl cGMP. Hemoglobin, which binds extracellular NO, also shortens the duration of stimulus-induced potentiation. The results suggest a role for NO in the maintenance of activity-dependent synaptic enhancements, possibly via the generation of cGMP.

Mutant mice and neuroscience: Recommendations concerning genetic background

The following scientists made significant contributions to the recommendations in this article:

Inhibition of nitric oxide synthesis impairs two different forms of learning

Nitric oxide (NO), an intercellular messenger in the central nervous system of vertebrates, plays an important role in the establishment of synaptic plasticity. In order to investigate the role of NO and synaptic plasticity in learning, we injected rats and rabbits with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) prior to training on two tests of learning. Rats treated with L-NAME were impaired in learning a spatial learning task, while rabbits given the NO synthase inhibitor demonstrated learning deficits in the conditioned eyeblink response. The results support the hypothesis that NO plays a critical role in acquisition of two different forms of learning.

Is the Ras-MAPK signalling pathway necessary for long-term memory formation?

Genetic and pharmacological experiments have recently implicated several protein kinase cascades in LTP and memory formation. The small GTPases of the Ras subfamily are activated by multiple extracellular stimuli and, via a complex array of downstream effectors, they control a variety of cellular events that culminate in gene transcription. In the well-characterized Aplysia gill-withdrawal reflex, activation of the Ras-dependent mitogen-activated protein kinase (MAPK) cascade is essential for the long-term, but not the short-term, facilitation process. In addition, in the rodent hippocampus, specific inhibition of the MAPK pathway significantly impairs the induction of LTP, which implicates this signalling cascade in hippocampal-dependent behaviour. Mice that lack the neuronal-specific Ras regulator, Ras-GRF (guanine-releasing factor), have severely impaired LTP in the amygdala and a corresponding deficit in long-term memory for aversive events. The results obtained from these different systems demonstrate the involvement of Ras-dependent signalling in neuronal plasticity and behaviour and raise a number of intriguing questions.

Impaired learning in mice with abnormal short-lived plasticity

BACKGROUND Many studies suggest that long term potentiation (LTP) has a role in learning and memory. In contrast, little is known about the function of short-lived plasticity (SLP). Modeling results suggested that SLP could be responsible for temporary memory storage, as in working memory, or that it may be involved in processing information regarding the timing of events. These models predict that abnormalities in SLP should lead to learning deficits. We tested this prediction in four lines of mutant mice with abnormal SLP, but apparently normal LTP-mice heterozygous for a alpha-calcium calmodulin kinase II mutation (alpha CaMKII +/-) have lower paired-pulse facilitation (PPF) and increased post-tetanic potentiation (PTP); mice lacking synapsin II (SyII-/-), and mice defective in both synapsin I and synapsin II (SyI/II-/-), show normal PPF but lower PTP; in contrast, mice just lacking synapsin I (SyI-/-) have increased PPF, but normal PTP. RESULTS Our behavioral results demonstrate that alpha CaMKII +/-, SyII-/- and SyI/II-/- mutant mice, which have decreased PPF or PTP, have profound impairments in learning tasks. In contrast, behavioral analysis did not reveal learning deficits in SyI-/- mice, which have increased PPF. CONCLUSIONS Our results are consistent with models that propose a role for SLP in learning, as mice with decreased PPF or PTP, in the absence of known LTP deficits, also show profound learning impairments. Importantly, analysis of the SyI-/- mutants demonstrated that an increase in PPF does not disrupt learning.

The α-Ca2+/calmodulin kinase II: A bidirectional modulator of presynaptic plasticity

The alpha-Ca2+/calmodulin kinase II (alpha CaMKII) is required for long-term potentiation in the CA1 region of the hippocampus. Here, we report that this kinase also has a crucial role in presynaptic plasticity. Paired-pulse facilitation is blunted in the CA1 region of mice heterozygous for a targeted mutation of alpha CaMKII, confirming that this kinase can promote neurotransmitter release. Unexpectedly, field and whole-cell recordings of posttetanic potentiation show that the synaptic responses of mutants are larger than those of controls, indicating that alpha CaMKII can also inhibit transmitter release immediately after tetanic stimulation. Thus, alpha CaMKII has the capacity either to potentiate or to depress excitatory synaptic transmission depending on the pattern of presynaptic activation.

Genes, models and Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.

Nitric oxide synthase inhibitors block long-term potentiation induced by weak but not strong tetanic stimulation at physiological brain temperatures in rat hippocampal slices

Nitric oxide synthase (NOS) inhibitors have been shown to block long-term synaptic enhancements in the mammalian hippocampus. This effect has been somewhat controversial, however, showing sensitivity to both temperature and stimulus strength. We have demonstrated a differential effect of the NOS inhibitor L-NG-nitroarginine (NOArg) on long-term potentiation (LTP) induced by weak and strong tetanic stimulation in slices of rat hippocampus. NOArg prevented LTP induction by a weak tetanus that produced stable potentiation in control slices, while the NOS inhibitor was without effect when strong tetani were used. These results suggest that nitric oxide (NO) produced as a result of tetanic stimulation plays a role in adjusting the threshold of LTP induction, but is not necessary for establishing synaptic enhancement under conditions of strong synaptic activation.