Age-related changes in medial septal cholinergic and GABAergic projection neurons and hippocampal neurotransmitter receptors: relationship with memory impairment.

The hippocampus, which provides cognitive functions, has been shown to become highly vulnerable during aging. One important modulator of the hippocampal neural network is the medial septum (MS). The present study attempts to determine how age-related mnemonic dysfunction is associated with neurochemical changes in the septohippocampal (SH) system, using behavioral and immunochemical experiments performed on young-adult, middle-aged and aged rats. According to these behavioral results, the aged and around 52.8% of middle-aged rats (within the "middle-aged-impaired" sub-group) showed both impaired spatial reference memory in the Morris water maze and habituation in the open field. Immunohistochemical studies revealed a significant decrease in the number of MS choline acetyltransferase immunoreactive cells in the aged and all middle-aged rats, in comparison to the young; however the number of gamma-aminobutyric acid-ergic (GABAergic) parvalbumin immunoreactive cells was higher in middle-aged-impaired and older rats compared to young and middle-aged-unimpaired rats. Western Blot analysis moreover showed a decrease in the level of expression of cholinergic, GABAergic and glutamatergic receptors in the hippocampus of middle-aged-impaired and aged rats in contrast to middle-aged-unimpaired and young rats. The present results demonstrate for the first time that a decrease in the expression level of hippocampal receptors in naturally aged rats with impaired cognitive abilities occurs in parallel with an increase in the number of GABAergic neurons in the MS, and it highlights the particular importance of inhibitory signaling in the SH network for memory function.

Modulation of spatial memory and expression of hippocampal neurotransmitter receptors by selective lesion of medial septal cholinergic and GABAergic neurons.

The medial septum (MS) is an important modulator of hippocampal function. The degree of damage in which the particular set of septo-hippocampal projections contributes to the deficits of spatial memory with concomitant changes of hippocampal receptors expression has not been studied till present. Therefore, we investigated spatial memory and the expression level of cholinergic (α7 nACh and M1), GABAergic (α1 subunit of GABAA) and glutamatergic (NR2B subunit of NMDA and GluR 1 subunit of AMPA) receptors in the hippocampus following selective lesions of cholinergic and GABAergic septo-hippocampal projection. Learning process and long-term spatial memory were assessed using a Morris water maze. The obtained results revealed that in contrast to cholinergic lesions, rats with MS GABAergic lesions exhibit a retention deficit in 3 days after training. Western blot analyses revealed the MS cholinergic lesions have significant effect on the expression level of the M1 mACh receptors, while MS GABAergic lesions induce dramatic modulations of hippocampal glutamatergic, cholinergic and GABAergic receptors expression. These results for the first time demonstrated that selective lesions of MS cholinergic and GABAergic neurons differentially affect long-term spatial memory and the memory deficit after MS GABAergic lesion is paralleled with significant changes of hippocampal glutamate, GABA and acetylcholine receptors expression.

Memantine treatment prevents okadaic acid induced neurotoxicity at the systemic and molecular levels.

The present study was designed to investigate the effects of okadaic acid intracerebroventricular (ICV) injection on memory function and expression level of α7 subunit of nicotinic acetylcholine receptor (nAChR) and NR2B subunit of NMDA glutamate receptors in the hippocampus, as well as effect of the antidementic drug memantine on okadaic acid induced changes at systemic and molecular levels in rats. Okadaic acid was dissolved in artificial cerebrospinal fluid (aCSF) and injected ICV 200 ng/10 µl. Vehicle control received 10 µl of aCSF ICV bilaterally. Control and okadaic acid injected rats were divided into two subgroups: treated i.p. with saline or memantine (5 mg/kg daily for 13 days starting from the day of okadaic acid injection). Rats were trained in the dual-solution plus-maze task that can be solved by using place or response strategies. The Western immunoblotting was used to determine relative amount of hippocampal receptors protein levels. Obtained data revealed that okadaic acid ICV injected rats were severely impaired at acquiring the place version of the maze accompanied by significant decline in hippocampal α7 subunit of nACh receptors protein levels. Memantine treatment can prevent okadaic acid induced impairment of hippocampal-dependent spatial memory and accompanied by modulation of the expression level of α7 subunit of nACh and NR2B subunit of NMDA receptors in the hippocampus. Thus, our results support the presumption that α7 nACh receptors may play an important role in the cognitive enhancer effects of memantine and emphasize the role of cholinergic-glutamatergic interactions in memory.