Alzheimers disease (AD) is a prevalent neurodegenerative disorder in the elderly. AD develops progressively with cognitive impairment and behavioral disorders characterized by loss of memory. Besides memory, it is now well accepted that cognitive and executive functions, predominantly those mediated by limbic areas, are also significantly affected in AD. These limbic areas play critical roles in elaborating thoughts, behavior, and emotions using working memory. Interestingly, the nucleus accumbens (nAc) was found to be affected by amyloid deposits and dystrophic neurites. Although acute A? can inhibit the release of dopamine in the nAc, the mechanism for this action is still unknown. A possibility is that this effect might be produced by alterations in diverse neurotransmissions, in a time dependent manner. We published several studies providing mechanistic information to explain the synaptic depletion caused by A?. Also, we reported that low concentrations of ethanol have an inhibitory effect on the cytotoxic effects of A? because 10 mM ethanol affects formation of ? sheets and oligomerization. Thus, depending on the concentration and exposure time, ethanol might have positive and negative outcomes in AD. This study will initiate the examination of acute effects of ethanol on a limbic region important for AD symptoms, and then proceed towards establishing a chronic paradigm. We showed for the first time that glycine receptors (GlyRs) were reversibly potentiated in mammalian spinal neurons. Recently, it was suggested that GlyRs in nAc might be implicated in ethanol intake behaviors. It is widely accepted that elevation in dopamine increases motivation for drug consumption, which eventually may lead to dependence and addiction. A role of GlyRs in motivation is supported by studies showing that similar to other addictive drugs, ethanol increases dopamine (DA) in the mesolimbic system, an effect that was blocked by strychnine. Recently, data from our laboratory showed that GlyRs in nAc D1 MSN are conformed by ?1 and ?2 subunits that are sensitive to ethanol. Because GlyRs activation is inhibitory in D1 MSNs and GlyRs likely antagonize excitatory neurotransmission, they might counteract rewarding actions of acute ethanol.
Our specific aim 1 will be to determine if ethanol and A? affect the function of the GlyR in nAc MSNs in an antagonistic fashion. Therefore, we will use patch clamp to record the activity of GlyR in D1-GFP MSNs. The effects of oligomeric A? will be studied in dissociated and brain slices exposed to acute applications of this neurotoxic peptide. We will characterize the properties of synaptic and non-synaptic GyRs in MSNs that are critical for elaborating thoughts, behavior, and emotions. Thereafter, we will proceed to specific aim 2 where we will evaluate the effects of intracellular A? on the physiology of MSNs during the application of the neurotoxic peptide. We will determine effects on synaptic transmissions mediated by AMPA, NMDA and GABAA receptors. We expect that A? will affect the function of GlyRs and synaptic transmission thereby demonstrating a new brain target and help to explain signs and symptoms seen in AD patients. Ethanol, depending on time and concentration, might enhance or inhibit the toxicity of A?. !
The global aging of the world population will result in more cases of Alzheimers disease further increasing social and economic burden. Therefore, it is urgent to develop a better understanding of the sites and mechanisms related to the synaptic dysfunctions associated to the disease. Thus, the type of research that we propose to carry out will serve to understand the synaptic basis for alterations in cognitive and executive functions that are regulated by limbic areas like the nucleus accumbens which are significantly affected in AD.
