Neuroprotective effect of estradiol in mice with selective cholinergic lesions in nucleus basalis magnocellularis: morphological and behavioural studies

Basal forebrain cholinergic (BFC) neurons play a critical role in learning and memory and are highly affected in the age-associated neurodegenerative disorders such as Alzheimer’s disease (AD). Previous neurodegenerative lesion studies have demonstrated a neuroprotective effect of gonadal steroid,17β-estradiol (E2), treatment on cholinergic neurons. However, these lesion models lacked selective damage to cholinergic neurons, limiting the interpretation of behavioural deficits observed after such a lesion and the correlation with the neuroprotective potential of E2. In this study, we have examined the effect of E2 treatment on cholinergic neurons and associated learning behaviours using an in vivo mouse model with a selective cholinergic lesion in the nucleus basalis magnocellularis (NBM). Such a model was achieved by applying a novel, highly selective mouse cholinotoxin, mu p75-Saporin (mp75SAP), by means of a microinjection into the NBM of ovariectomised adult female mice. Unilateral injection of mp75-SAP resulted in cholinergic cell loss in the NBM and ipsilateral cholinergic fibre loss in the somatosensory cortex. The 0.9μg/μl mp75-SAP exhibited ~70% of cholinergic cell loss in the NBM and ~75% of cholinergic fibre loss in the cortex. A single injection of E2 1h after mp75SAP-induced lesion increased the ipsilateral cholinergic fibre density in the somatosensory cortex by approximately 10% but did not have an effect on cholinergic cell loss in the NBM. The functional consequences of an E2 treatment on selective cholinergic lesion in the NBM was tested by performing a single-pellet skilled-reaching task and a novel object recognition test which tested the animals’ learning behaviours. Mice given a bilateral injection of mp75SAP into the NBM demonstrated profound learning deficits in both tests. The acute E2 treatment did not have an effect on the mp75SAP lesion-induced learning deficits. However, the cholinergic fibres in the somatosensory cortex were restored by the E2 treatment following bilateral mp75SAP-induced cholinergic lesion in the NBM. These findings demonstrate that a single E2 treatment is able to restore the basal forebrain fibre loss in the somatosensory cortex following the cholinergic lesion in the NBM, but does not have any functional effect regarding the motor skill and discrimination learning behaviours. Overall, this study aids in understanding of E2-induced neuroprotective actions that may have therapeutic relevance in AD-associated BFC degeneration and progressive cognitive decline