Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice

Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its neuroprotective and neurotrophic properties. This study used modern stereological techniques to investigate possible CA1 pyramidal neuron loss in 11-month-old triple transgenic AD (3xTg-AD) mice, and also the effects of therapeutic and subtherapeutic lithium doses on the number and density of CA1 pyramidal neurons and volume of CA1 pyramidal layer in 3xTg-AD and wild-type mice treated from 3 to 11 months of age. 3xTg-AD mice displayed CA1 pyramidal layer atrophy that is likely due to reduced neuronal volume because of the absence of neuronal loss. Both lithium treatments of 3xTg-AD mice, which already expressed AD-like pathology, had no effect on CA1 atrophy. However, lithium treatment of wild-type mice, at low (subtherapeutic) doses, induced a significant increase in total CA1 pyramidal neuron number that led to a significant increase in total CA1 pyramidal layer volume. The lithium-induced increase in CA1 neuron number is highly consistent with previous evidence that adult neurogenesis can be exogenously induced in the CA1 pyramidal layer with impact on total CA1 neuron number, thus raising the possibility of the chronic use of low-dose lithium as a strategy to help compensate for neuronal loss in CA1 and perhaps other typically non-neurogenic brain regions in various neurological diseases. With regard to AD, low-dose lithium intervention must be initiated as early as possible in the course of neuropathology for beneficial effects to occur.