Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures

Abstract

Alzheimer's disease is the most common form of dementia in North America today. Though many risk factors have been suggested to increase the likelihood of developing this disease, an accurate etiology has yet to be described. One of these risk factors commonly associated with Alzheimer's disease is the loss of cholinergic neurons of the medial septum that project to the hippocampus, leading to depletion in cholinergic activity. A second risk factor is the presence of seizures, which can increase the risk of excitotoxic cell death. To examine the interaction between these two common risk factors, we gave rats a focal cholinergic lesion of the medial septum using the specific immunotoxin 192-IgG Saporin, followed 2 weeks later by a non-convulsive dose of kainic acid. We then assessed the rats for seizure severity, hippocampal damage and performance on a spatial memory task. The combination of the two factors resulted in a trend towards increased seizure severity in the cholinergic depleted rats, but more importantly, the lesioned rats that had non-convulsive seizures were significantly impaired on a spatial version of the Morris water maze when compared with either the rats with a cholinergic depletion or non-convulsive seizure alone. This result could not be explained by seizure severity or the extent of hippocampal damage, suggesting a more subtle interaction between these two risk factors in the development of a hippocampal based memory impairment.

Loss of Medial Septum Cholinergic Neurons in THY-Tau22 Mouse Model: What Links with tau Pathology?

“…Cholinergic neurotransmission is known to regulate synaptic plasticity and to play a role in memory behavior [17,43,44]. In line, cholinergic depletion decreases adult neurogenesis [45] and increases the vulnerability of hippocampal neurons to insult thereby contributing to the appearance of hippocampaldependent spatial memory deficits [46,47]. It is thus reasonable to propose that the cholinergic neuronal loss observed in the THY-Tau22 model may emphasize the hippocampal dysfunction primarily caused by tau pathology and contributes significantly to the observed cognitive impairments.…”

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology

“…Indeed, we found that long-term voluntary exercise prevented the loss of ChAT immunoreactive neurons observed in the medial septum of THY-Tau22 mice. Cholinergic neurotransmission promotes hippocampal synaptic plasticity (Doralp and Leung, 2008;Ji and Dani, 2000;Ovsepian et al, 2004), and the depletion of medial septal cholinergic neurons increases the vulnerability of hippocampal neurons to insult and favors the appearance of hippocampus-dependent spatial memory deficits (Craig et al, 2008;Jolkkonen et al, 1997). Thus, it is reasonable to suggest that the prevention of cholinergic alterations by exercise contributes to the impact of exercise on memory performance in THY-Tau22 model.…”

Kainic acid lesion-induced spatial memory deficits of rats

“…In rats with bilaterally specific lesion of hippocampus dorsal CA1 and ventral CA3 subregions, KA induced deficits in acquisition of the water maze task and significant memory impairment of the passive avoidance task, suggesting effects on spatial memory and associative memory [17]. In other study, it has been shown that reduced cholinergic status in hippocampus produced spatial memory deficits of rats in water maze task when combined with KA induced seizure [18]. Intrahippocampal injection of KA in rats induced impaired acquisition and retention of visual-spatial information in water-maze task, suggesting spatial cognitive alterations [19].…”