Synaptic dysfunction

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

Oddo, S., Caccamo, A., Shepherd, J. D. et al. Triple-transgenic model of Alzheimer s disease with plaques and tangles intracellular AP and synaptic dysfunction. Neuron 39 409 21,2003. 

D. A. Forero, G. Casadesus, G. Perry, and H. Arboleda. Synaptic Dysfunction and Oxidative Stress in Alzheimer s Disease Emerging Mechanisms. J. Cell. Mol. Med., 10(2006) 796-805. 

Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed, R., Metherate, R., Mattson, M.P., Akbari, Y., and LaFerla, F.M., Triple-transgenic model of Alzheimer s disease with plaques and tangles intracellular Abeta and synaptic dysfunction, Neuron, 39, 409, 2003. 

Another mechanism of synaptic dysfunction in AD may involve amyloid ft peptide (Aft a 40 to 42 amino acid peptide). A marked increase in Aft levels occurs in brain tissue from AD patients. A ft inhibits glutamatergic neurotransmission and reduces synaptic plasticity (Snyder et al., 2005). Treatment of cortical neuronal cultures with Aft facilitates endocytosis of NMDA receptor. Aft-mediated endo-cytosis of NMDA receptor requires the a-1 nicotinic receptor, protein phosphatase 2B, and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyrl472 correlates with receptor endocytosis. The addition of a y-secretase inhibitor not only reduces Aft but also restores surface expression of NMDA receptors, suggesting that A plays an important role in the regulation of NMDA and AMPA receptor trafficking (Snyder et al., 2005 Morishita et al., 2005). 

Because of their critical role in neurotransmitter release, SNARE proteins represent a potential molecular substrate for synaptic dysfunction or misconnectivity. Accordingly, a number of postmortem studies have reported changes in the level of expression for SNARE proteins in schizophrenia. 

Patients often have memory deficits after taking benzodiazepines and alcohol. In a study of hippocampal pre-synaptic glutamate transmission in conjunction with memory deficits induced by benzodiazepines and ethanol, reductions in hippocampal glutamate transmission closely correlated with the extent of impairment of spatial memory performance. The results strongly suggested that pre-synaptic dysfunction in dorsal hippocampal glutamatergic neurons would be critical for spatial memory deficits induced by benzodiazepines and ethanol (85). 

Of particular interest is that the A6 oligomers implicated in AD were shown to reduce PAKl and PAK3 expression levels and activities in the hippocampus and temporal cortex, resulting in a loss of drebrin from the spines and synaptic dysfunctions (Zhao et al., 2006 Ma et al., 2008). Drebrin is localized at spines in adult brains and is required for active clustering and synaptic targeting of PSD95... 

The role of tau in synaptic dysfunction has not been as well documented as A. Tau has been reported to change intracellular calcium levels, probably via the interaction of extracellular tau with muscarinic receptors Ml and M3 (G6mez-Ramos et al., 2008). Also a spatially association of tau modifications with intraneuronal AP, in which both pathologies co-occur at synaspses has been reported (Takahashi et al., 2010). Finally, using two-photon calcium imaging in layer 2/3 of an AD mouse model cortical neurons, an increase in the frequency of spontaneous calcium transients in the vicinity of amyloid plaques was seen (Busche et al., 2008). 

The possible future directions of AD research may include (a) more detailed information in the synaptic dysfunction (i.e., localizing the pre- and postsynap-tic events, identification of the toxic tau subspecies and its molecular pathway) ... 

Homocystine may induce Ap accumulation, synaptic dysfunction, and memory impairment. Lu et al. [581] reported that Hydroxysafflor Yellow A (HSYA) attenuates Ap accumulation, improves synaptic function, and reverses homocysteine-induced cognitive impairment. 

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