Neurobiological and Endocrine Correlates of Individual Differences in Spatial Learning Ability

Recent data suggest that Alzheimer's 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 diseasemodifying 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 memoryassociated 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.

Section: Discussionmentioning

confidence: 99%

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Murphy

Foley

O’Connell

et al. 2005

“…Given that the frequency of dentate polysialylated neurons transiently increase at the 12 h post-training time during the consolidation of a variety of learning paradigms (Fox et al, 1995;Murphy et al, 1996;Foley et al, 2003a;Sandi et al, 2003), and that the extent of this increase is commensurate with complexity experienced in consolidating the task (Sandi et al, 2004;Murphy et al, 2006), we determined whether GSK189254-induced increases in basal polysialylated cell expression could be further enhanced at the 12 h post-training time after water maze training. Separate cohorts of animals were treated with either vehicle or GSK189254 (0.3 mg/kg) for 4 days and trained in the water maze paradigm at 2 h after the final drug treatment.…”

Section: Spatial Learning-induced Activation Ncam Psa State In the Dementioning

confidence: 99%

“…The consolidation of many behavioral tasks is now known to require a transient increase in the frequency of polysialylated neurons, notably at the 12 h post-training time, in the hippocampal dentate gyrus (Fox et al, 1995 [84] Murphy et al, 1996;Foley et al, 2003a;Sandi et al, 2003Sandi et al, , 2004 and associated entorhinal and perirhinal cortex (O'Connell et al, 1997;Fox et al, 2000). Moreover, disruption of PSA function, by intraventricular infusion endoneuraminidase-N or anti-PSA, impairs task consolidation (Becker et al, 1996;Muller et al, 1996;Venero et al, 2006;Lopez-Fernandez et al, 2007;Seymour et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

H3 Receptor Antagonism Enhances NCAM PSA-Mediated Plasticity and Improves Memory Consolidation in Odor Discrimination and Delayed Match-to-Position Paradigms

Foley

Prendergast

Barry

et al. 2009

To further understand the procognitive actions of GSK189254, a histamine H 3 receptor antagonist, we determined its influence on the modulation of hippocampal neural cell adhesion molecule (NCAM) polysialylation (PSA) state, a necessary neuroplastic mechanism for learning and memory consolidation. A 4-day treatment with GSK189254 significantly increased basal expression of dentate polysialylated cells in rats with the maximal effect being observed at 0.03-0.3 mg/kg. At the optimal dose (0.3 mg/kg), GSK189254 enhanced water maze learning and the associated transient increase in NCAM-polysialylated cells. The increase in dentate polysialylated cell frequency induced by GSK189254 was not attributable to enhanced neurogenesis, although it did induce a small, but significant, increase in the survival of these newborn cells. GSK189254 (0.3 mg/kg) was without effect on polysialylated cell frequency in the entorhinal and perirhinal cortex, but significantly increased the diffuse PSA staining observed in the anterior, ventromedial, and dorsomedial aspects of the hypothalamus. Consistent with its ability to enhance the learning-associated, post-training increases in NCAM PSA state, GSK189254 (0.3 mg/kg) reversed the amnesia induced by scopolamine given in the 6-h post-training period after training in an odor discrimination paradigm. Moreover, GSK189254 significantly improved the performance accuracy of a delayed match-to-position paradigm, a task dependent on the prefrontal cortex and degree of cortical arousal, the latter may be related to enhanced NCAM PSA-associated plasticity in the hypothalamus. The procognitive actions of H3 antagonism combined with increased NCAM PSA expression may exert a disease-modifying action in conditions harboring fundamental deficits in NCAM-mediated neuroplasticity, such as schizophrenia and Alzheimer's disease.

“…NCAM expression and its posttranslational polysialylation, which decreases the adhesive strength of NCAM, are critically involved in memory formation and activity-dependent synaptic remodeling processes (Doyle et al, 1992b;Lüthi et al, 1994;Rose, 1995;Arami et al, 1996;Becker et al, 1996;Foley et al, 2000;Welzl and Stork, 2003). Learning is also characterized by altered expression and glycosylation of NCAM (Doyle et al, 1992a;Rusakov et al, 1994;O'Connell et al, 1997;Tiunova et al, 1998;Sandi et al, 2004). Targeted disruption of the NCAM gene resulted in learning deficits (Cremer et al, 1994;Stork et al, 2000) accompanied by alterations in emotional/ motivational behavior and by hyperresponsiveness of the serotonergic system (Stork et al, 1999(Stork et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

Exposure to Stressors during Juvenility Disrupts Development-Related Alterations in the PSA-NCAM to NCAM Expression Ratio: Potential Relevance for Mood and Anxiety Disorders

Tsoory

Guterman

Richter‐Levin

2007

Childhood trauma is associated with higher rates of both mood and anxiety disorders in adulthood. The exposure of rats to stressors during juvenility has comparable effects, and was suggested as a model of induced predisposition for these disorders. The neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM are critically involved in neural development, activity-dependent synaptic plasticity, and learning processes. We examined the effects of exposure to stressors during juvenility on coping with stressors in adulthood and on NCAM and PSA-NCAM expression within the rat limbic system both soon after the exposure and in adulthood. Exposure to stressors during juvenility reduced novel-setting exploration and impaired two-way shuttle avoidance learning in adulthood. Among naive rats, a development-related decrease of about 50% was evident in the PSA-NCAM to NCAM expression ratio in the basolateral amygdala, in the CA1 and dentate gyrus regions of the hippocampus, and in the entorhinal cortex. In juvenile-stressed rats, we found no such decrease, but rather an increase in the polysialylation of NCAM (B50%), evident soon after the exposure to juvenile stress and also in adulthood. Our results suggest that exposure to stressors during juvenility alters the maturation of the limbic system, and potentially underlies the predisposition to exhibit stress-related symptoms in adulthood.