Alan W. O'Connell

Repetitive and Transient Increases in Hippocampal Neural Cell Adhesion Molecule Polysialylation State Following Multitrial Spatial Training

Abstract: Polysialylated neurons, located at the inner border of the dentate granule cell layer, have been demonstrated to exhibit time‐dependent change in their frequency at 10–12 h following training in the Morris water maze, a spatial learning paradigm. Such a change was not observed in animals required to locate a visible platform or in those rendered amnesic with scopolamine. This frequency response was capable of rapid reactivation following further training stimuli in a manner that was independent of circadian influence. These learning‐associated modulations in neural cell adhesion molecule (NCAM) polysialylation state did not increase in magnitude despite improved performance, suggesting their activation is required for processing information rather than contributing to previously stored, task‐associated memory. An increase in NCAM polysialylation appears to be a universal learning response to both spatial and nonspatial paradigms as similar time‐dependent changes occurred following training in a one‐trial, step‐through, passive avoidance response subsequent to water maze training.

Memory consolidation induces a transient and time-dependent increase in the frequency of neural cell adhesion molecule polysialylated cells in the adult rat hippocampus.

Abstract: Animals trained in a passive avoidance task exhibit a transient time‐dependent increase in hippocampal neural cell adhesion molecule (NCAM) polysialylation at 12–24 h following the initial learning trial. Using immunocytochemical techniques with a monoclonal antibody that specifically recognises NCAM‐polysialic acid homopolymers, a distinct population of granule‐like cells, at the border of the granule cell layer and the hilus in the dentate gyrus of the adult rat hippocampus, has been demonstrated to exhibit time‐dependent change in frequency at 10–12 h following the initial learning of a one‐trial, step‐through, passive avoidance response. These changes were paradigm specific as they failed to occur in those animals rendered amnesic with scopolamine. These polysialylated dentate neurons are not de novo granule cell precursors as administration of 5‐bromo‐2′‐deoxyuridine every 2 h from the point of learning to the 12‐h posttraining time showed no significant difference between trained and passive animals in the small number of heterogeneously distributed, labelled cells. These findings directly identify a morphological substrate of memory, implied by previous correlative and interventive studies on NCAM function.

Spatial learning activates neural cell adhesion molecule polysialylation in a corticohippocampal pathway within the medial temporal lobe

Abstract: Transient and time‐dependent modulations of neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus of the rodent hippocampus are a feature of spatial and nonspatial forms of learning. In the hippocampal formation, polysialic acid immunoreactivity was localized to granule‐like cells and their mossy fibre axons. We now demonstrate the latter to extend to the CA3 region where apparent recurrent and Schaffer collaterals were labelled. The axons of the CA1 pyramidal cell layer were immunopositive, as was the subiculum that they innervate. Layers I and III of the entorhinal cortex stained intensely for polysialic acid; however, these were not visible in the more lateral aspect of this region and were replaced by a single band of immunopositive neurons that extended to include the perirhinal and piriform cortices. After Morris water maze training, the number of polysialylated neurons within the entorhinal cortex exhibited a two‐ to threefold increase at the 10–12‐h posttraining time with respect to that observed immediately after training. This increase was task specific, as no change was observed in freely swimming animals or those required to locate a visible platform. These results suggest the presence of a corticohippocampal pathway involved in the eventual consolidation of memory.

Polysialylated neural cell adhesion molecule expression in the dentate gyrus of the human hippocampal formation from infancy to old age

Modulation of neural cell adhesion molecule polysialylation (NCAM PSA) state has been proposed to underlie morphofunctional change associated with consolidation of memory in the rodent, and its age‐dependent decline to be related to impaired cognitive function. To establish whether this may be a human correlate of cognitive decline, we determined the age‐dependent expression of PSA in the human hippocampal dentate gyrus using postmortem tissue derived from individuals who exhibited no obvious neuropathology. As in the rodent, PSA immunoreactivity in the 5‐month human infant was associated mainly with a population of granule‐like cells and their mossy fibre axons. Cell numbers were maximal during the first 3 years of life but declined by an order of magnitude between the second and third decades and remained relatively constant thereafter and was restricted to the granule cell layer/hilar border. In contrast to the rodent, diffuse immunostaining was observed in the inner molecular layer; however, as development advanced, this became relocated to the outer molecular layer from 2 years of age onwards. In addition, numerous polysialylated hilar neurons became evident at 2–3 years of age and remained constant until the eighth decade of life. These findings suggest NCAM polysialylation to play a crucial developmental role within a period concluding with adolescence, and that an attenuated NCAM PSA‐mediated neuroplasticity continues throughout the human lifespan. The importance of the developmental phase of NCAM PSA expression in the emergence of schizophrenia is discussed. J. Neurosci. Res. 55:99–106, 1999. 

Pentyl-4-yn-valproic acid enhances both spatial and avoidance learning and attenuates age-related NCAM-mediated neuroplastic decline within the rat medial temporal lobe

2‐N‐Pentyl‐4‐pentynoic acid [pentyl‐4‐yn‐valproic acid (VPA)] is an analogue of valproic acid that induces neuritogenesis and increases neural cell adhesion molecule (NCAM) prevalence in cultured neural cells. As memory consolidation involves synapse growth, aided by cell adhesion molecule function, we determined whether or not pentyl‐4‐yn‐VPA had cognition‐enhancing properties. Pentyl‐4‐yn‐VPA (16–85 mg/kg) significantly improved water maze learning and task retention when given prior to each training session. Acute administration of pentyl‐4‐yn‐VPA also influenced memory consolidation processes as, when given at 3 h post‐passive avoidance training, the amnesia induced by scopolamine given 6 h post‐training was prevented in a dose‐dependent manner. Chronic administration of pentyl‐4‐yn‐VPA (16.8 or 50.4 mg/kg) also significantly reduced escape latencies in the water maze task, 24 h following the last drug administration. This improved spatial learning was accompanied by enhanced neuroplasticity as the expression of NCAM polysialylated neurons in the infragranular zone of the dentate gyrus and in layer II of the perirhinal and piriform cortex was increased significantly following chronic drug treatment. The cognition‐enhancing qualities of pentyl‐4‐yn‐VPA, combined with its ability to attenuate the age‐related loss of the NCAM polysialylation state, suggest that it may effectively slow the onset of cognitive decline.

Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

Recent data suggest that Alzheimers patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

Nefiracetam prevents propofol-induced anterograde and retrograde amnesia in the rodent without compromising quality of anesthesia.

Background Propofol is a short-acting intravenous anesthetic agent. However, cognitive function remains depressed for several hours thereafter. We have evaluated the ability of nefiracetam, a novel cognition-enhancing agent, to alleviate propofol-induced amnesia in a rodent model of learning. Methods Rats were trained in a one-trial, step-through, light-dark passive avoidance paradigm. Propofol (10 and 75 mg/kg) was administered by the intraperitoneal route at 15 min before training and separately at increasing times in the immediate 0 - 6 h post-training period (100 and 150 mg/kg). Nefiracetam, 9 mg/kg, was administered by the intraperitoneal route 1 h before training. Animals were tested for recall at the 12 h post-training time, and after their killing, immunocytochemistry was used to determine the increase in hippocampal neuronal polysialylation, an event associated with memory consolidation. Induction and duration of anesthesia induced by propofol was determined using tail pinch and pedal withdrawal reflexes. Results Propofol-induced anterograde amnesia occurred in a dose-dependent manner. Induction of retrograde amnesia required a higher dose of propofol, which anesthetized the animals and was effective only in the immediate 3-h post-training period. In the absence of any evidence effect on the onset or duration of anesthesia, nefiracetam prevented both forms of propofol-induced amnesia and preserved the learning-associated changes of neuronal polysialylation state. Conclusions The ability of nefiracetam to prevent propofol-induced anterograde and retrograde amnesia is proposed to be indirect and to result from modulation of gene transcription in a manner that initiates a cascades of events involving protein synthesis leading to synaptic growth associated with the formation of the long-term memory trace.

Influence of nefiracetam on NGF-induced neuritogenesis and neural cell adhesion molecule polysialic acid expression: in vivo and in vitro comparisons

Previously, the ability of co-administered nefiracetam to reverse scopolamine-induced learning deficits has been attributed to the preservation of a transient increase in neural cell adhesion molecule (NCAM) polysialylation state during a late phase of memory consolidation (Doyle et al., J. Neurosci. Res., 31 (1992) 513-523). Using the PC-12 pheochromocytoma cell model, we now demonstrate nefiracetam pre-exposure to significantly enhance nerve growth factor-induced neuritogenesis and NCAM polysialylation, but not prevalence, in a dose-dependent manner with maximal effects being observed at the lowest dose (0.1 microM) examined. As the memory-associated increase in NCAM polysialylation in vivo is associated with a defined group of neurons at the dentate hilar/granule cell layer border (Regan and Fox, Neurochem. Res., 20 (1995) 521-526), the effect of chronic nefiracetam exposure in vivo was evaluated. Once-daily, intraperitoneal administration of either 3 or 9 mg/kg nefiracetam to adult male Wistar rats for 40 days significantly increased the number of hippocampal dentate polysialylated neurons only at the highest dose evaluated, suggesting it to prevent their age-dependent decline. These results are consistent with nefiracetam facilitating early induction events of long-term memory consolidation processes involving NCAM polysialylation state.