Stephen J. Martin

A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease

Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive β-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with β-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that Aβ overexpression and/or Aβ plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimers-disease-type pathologies.

Reversible neural inactivation reveals hippocampal participation in several memory processes

Studies of patients and animals with brain lesions have implicated the hippocampal formation in spatial, declarative/relational and episodic types of memory. These and other types of memory consist of a series of interdependent but potentially dissociable memory processes—encoding, storage, consolidation and retrieval. To identify whether hippocampal activity contributes to these processes independently, we used a novel method of inactivating synaptic transmission using a water-soluble antagonist of AMPA/kainate glutamate receptors. Once calibrated using electrophysiological and two-deoxyglucose techniques in vivo, drug or vehicle was infused chronically or acutely into the dorsal hippocampus of rats at appropriate times during or after training in a water maze. Our findings indicate that hippocampal neural activity is necessary for both encoding and retrieval of spatial memory and for either trace consolidation or long-term storage.

The rodent hippocampus and spatial memory: from synapses to systems

Abstract.Although its operations are not limited to the spatial domain, there is a near consensus that the hippocampus plays a critical role in memory for place. This review aims to explore this role, with a particular emphasis on the functions performed by distinct hippocampal subregions. The use of innovative lesioning techniques, localized pharmacological treatments, and molecular genetic interventions is offering increasingly precise brain-regional specificity and temporal control. Together with the electrophysiological recording of neuronal activity, these techniques are beginning to shed light on the functioning of specific components of the hippocampal circuitry in the different phases of memory — encoding, storage, consolidation, and retrieval. In view of these developments, we examine the involvement of the hippocampus in the encoding versus retrieval of spatial memory, before turning to the issue of long-term information storage and the role of ‘cellular’ and ‘system’ consolidation processes in the formation of lasting memories.

Interrogating rodents regarding their object and spatial memory.

Today, neuroscientists have access to a host of advanced techniques -- ranging from targeted genetic interventions to brain imaging -- that are rapidly providing new insights. Ultimately, however, memory must be inferred from its behavioral read-out. Thus, to fully utilize the advanced technologies available today, we must select the most appropriate behavioral procedures from those currently available, or else devise novel behavioral techniques to meet a specific demand. If we merely use standard tests of memory in a non-optimal way, we risk collecting incomplete information and reaching erroneous conclusions. Relevant to these issues, there have been substantial developments in the methods used to evaluate two of the most frequently studied forms of memory in the rodent -- recognition memory and spatial memory.

Active β-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of β-Amyloid

The behavioral and biochemical impact of active immunization against human β-amyloid (Aβ) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated Aβ42 occurred at monthly intervals from 7 months (“prevention”) or 11 months (“reversal”), followed by double-blind behavioral training at 16 months on a cued task, then serial spatial learning in a water maze. Using a 2 × 2 design, with Aβ42 adjuvanted with MPL-AF (adjuvant formulation of monophosphoryl lipid A) or MPL-AF alone, PDAPP mice were impaired compared with non-Tg littermates on two separate measures of serial spatial learning. Immunization caused no overall rescue of learning but limited the accumulation of total Aβ and Aβ42 levels in cortex and hippocampus by up to 60%. In immunized PDAPP mice, significant negative correlations were observed between hippocampal and cortical Aβ levels and learning capacity, particularly in the prevention study, and correlations between learning capacity and antibody titer. Moreover, a subset of PDAPP mice with very low Aβ levels (hippocampal Aβ levels of <6000 ng/g or cortical Aβ levels of <1000 ng/g) was indistinguishable from non-Tg controls. Mice in the prevention study were also rescued from cognitive impairment more effectively than those in the reversal study. The combination of variability in antibody response and differential levels of Aβ accumulation across the population of immunized PDAPP mice may be responsible for success in cognitive protection with only a subset of these animals, but the similarity to the findings of certain human vaccination trials is noteworthy.

Time-dependent reversal of dentate LTP by 5 Hz stimulation.

FIELD potential recordings were made from the dentate gyrus of urethane-anaesthetized rats in order to investigate the ability of 5 Hz stimulation to reverse long-term potentiation (LTP) induced by a high frequency tetanus. A 10 min train of 5 Hz was found to reverse LTP in a time-dependent fashion: as the interval between tetanus and 5 Hz was increased, LTP became progressively less susceptible to reversal. If 10 min or 30 min intervened between tetanization and 5 Hz stimulation, LTP was unaffected. These results indicate that dentate LTP in vivo exhibits a similar limited time window of vulnerability to reversal by low frequency stimulation to that previously reported in area CA 1in vitro.

N‐methyl‐d‐aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d‐AP5 interacts directly with the neural mechanisms of spatial learning

Three experiments were conducted to contrast the hypothesis that hippocampal N‐methyl‐d‐aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus‐dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug‐induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d‐AP5 (30 mm) at 0.5 μL/h were selectively impaired, relative to aCSF‐infused animals, in place but not cued navigation learning when they were trained during the 14‐day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d‐AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d‐AP5‐treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d‐AP5‐treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d‐AP5 in selected brain areas. In Experiment 3, rats treated with d‐AP5 showed a delay‐dependent deficit in spatial memory in the delayed matching‐to‐place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.

Synaptic tagging and capture in the living rat.

In isolated hippocampal slices, decaying long-term potentiation (LTP) can be stabilized, and converted to late-LTP lasting many hours, by prior or subsequent strong high-frequency tetanization of an independent input to a common population of neurons—a phenomenon known as ‘synaptic tagging and capture’. Here we show that the same phenomenon occurs in the intact rat. Late-LTP can be induced in CA1 during the inhibition of protein synthesis if an independent input is strongly tetanized beforehand. Conversely, declining early-LTP induced by weak tetanization can be converted into lasting late-LTP by subsequent strong tetanization of a separate input. These findings indicate that synaptic tagging and capture is not limited to in vitro preparations; the past and future activity of neurons plays a critical role in determining the persistence of synaptic changes in the living animal, thus providing a bridge between cellular studies of protein-synthesis-dependent synaptic potentiation and behavioural studies of memory persistence.

Watermaze performance after middle cerebral artery occlusion in the rat: the role of sensorimotor versus memory impairments

In rodent stroke models, investigation of deficits in spatial memory using the Morris watermaze may be confounded by coexisting sensory or motor impairments. To target memory specifically, we devised a watermaze protocol to minimize the impact of sensory and motor impairments in female Lister-hooded rats exposed to proximal electrocoagulation of the middle cerebral artery (MCAO). Rats were trained in a reference-memory task comprising 4 trials/day; trial 1 being a probe trial (platform absent for the first 60 seconds). Training ended once animals reached a strict criterion based on the probe-trial performance. Memory retention was tested 1, 7, and 28 days later. The MCAO did not affect the number of days to reach criterion during acquisition or the time spent in target quadrant during retention testing, compared with sham or unoperated rats. However, MCAO rats showed slightly poorer accuracy in crossing the platform location and increased thigmotactic swimming compared with controls. Our results show that spatial memory deficits are minimal in this rodent stroke model, and suggest that previously published watermaze impairments are attributable to sensory and motor deficits but not memory deficits. We recommend using probe trials and training to a predetermined performance criterion in future studies assessing watermaze memory deficits in rodent stroke models.

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: deficit in memory retrieval associated with increased sensitivity to interference?

Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimers disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13-16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimers disease, further supporting the validity of transgenic models of the disease.