Muscarinic cholinergic receptor antagonism impairs spatial memory retrieval and minimizes retrieval-induced alterations in matrix metalloproteinase-9

Abstract

Cholinergic dysfunction in the hippocampus causes memory impairment, and degradation of the forebrain cholinergic system has been implicated in several neurological disorders. One such disorder, Alzheimer’s Disease (AD) is associated with the abnormal expression of various proteins including matrix metalloproteinase-9 (MMP-9), an enzyme known to regulate hippocampus-dependent memory. Memory involves several stages including acquisition, consolidation, and retrieval, but the neurobiological correlates of retrieval have been studied much less than other stages of memory. We sought to investigate the potential relationship between cholinergic signaling and hippocampal MMP-9 expression and the involvement of each in spatial memory retrieval. We trained rats in the water maze until the task was well-learned, then, seven days later, we allowed some to retrieve the memory after an intracerebroventricular injection of scopolamine or vehicle. Western blot analysis of hippocampal tissue shows elevated levels of a truncated form of MMP-9 associated with spatial memory retrieval. Additionally, our results indicate that centrally administered scopolamine both impairs spatial memory retrieval and prevents retrieval-induced elevations in MMP-9. These findings provide evidence for a potential link between cholinergic dysregulation and abnormal MMP-9 levels seen in the brains of AD patients. An important, yet unresolved question is whether MMP-9 serves to support memory retrieval itself or if it is involved in maintaining the ongoing stability of a retrieved memory.