Effects of medial septum deep brain stimulation for memory recovery in a memory impaired rat model established by 192 IgG-saporin injection

Abstract

The possibility of using deep brain stimulation (DBS) for memory enhancement was recently reported; however, the mechanisms underlying its effects are not precisely understood. This study was performed to find the therapeutic effects and mechanism of DBS using a memory impaired rat model. First, a spatial memory impaired rat model mimicking the cholinergic deficit in Alzheimer’s disease was established. Second, the effects of medial septum (MS)-DBS on this memory impaired rat model were investigated. Furthermore, to detect the stage of the memory process that was affected, DBS was delivered at different times.

In the first experiment, 192 IgG-saporin was infused into the cerebral ventricle to cause selective cholinergic damage. Two weeks later, cholinergic denervation caused spatial memory impairment in the Morris water maze test and glucose hypometabolism of the cingulate cortex in the [F-18] fluorodeoxyglucose PET study. In the second experiment, a 60-Hz stimulation was delivered to the MS to confirm the therapeutic effects of MS-DBS. During the 2-week stimulation, MS-DBS enhanced spatial memory and increased the number of doublecortin immunopositive cells in the hippocampus. Next, to detect the stage of the memory process affected by MS-DBS, stimulation was delivered at different times: pre-stimulation, 5days of before the water maze test; training-stimulation, 5days after the start of the training phase for the water maze; probe-stimulation, 2 h of stimulation shortly before the probe test of the water maze. The most effective memory restoration occurred in the pre-stimulation group in which the latency of the training phase was similar to that of the normal group. Moreover, the pre-stimulation group had a better recalled of the platform position than the other stimulation groups. An increase in the level of brain derived neurotrophic factor (BDNF) was observed in the pre-stimulation group that was maintained in both the frontal cortex and hippocampus. The level of glutamic acid decarboxylase 65/67, an enzyme that catalyzes the decarboxylation of glutamate to GABA, was reduced in the hippocampus. However, acetylcholinesterase activity in the pre-stimulation group was not different from the lesion group. These results suggest that the spatial memory improvement associated with MS-DBS is mainly correlated with increased BDNF expression in the frontal cortex and hippocampus, rather than with direct electrical stimulation of cholinergic or GABAergic neurons in the hippocampus.

Taken together, the memory impairment caused by cholinergic denervation could be improved by MS-DBS (60Hz). Additionally, it has a significant correlation with the up-regulation of BDNF expression and neurogenesis. Based on the results of this study, the use of MS-DBS during the early stage of disease is thought to restore spatial memory impairments.