Abstract
Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-β plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms.
Highlights
Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as the accumulation of extracellular amyloid-β plaques, intra-neuronal neurofibrillary tangles formed by aberrantly phosphorylated tau, degeneration of neurites or neuronal loss (Terry et al, 1991; Arriagada et al, 1992; Selkoe, 2002; Coleman and Yao, 2003; Giannakopoulos et al, 2003; Saul et al, 2013)
In this group the presynaptic neurons were injected on day 3 in culture with KCl or were not injected; (b) a group of synaptic pairs in which the presynaptic neurons were injected on day 3 in culture with mRNA encoding Green fluorescent protein (GFP), cerulean, or cherrytagged double mutant-human tau containing missense mutations P301S and K257T (Shemesh et al, 2008); (c) like group b, but 1–2 h after tagged mt-htau mRNA microinjection, paclitaxel at a final concentration of 10 nM was added to the culture solution; and (d) the presynaptic neuron not injected with mt-htau mRNA, but rather exposed to 10 nM paclitaxel from day 3 after culturing
All groups were subjected to electrophysiological experiments in which the resting potential, input resistances (Rin) and three synaptic parameters were monitored: (a) the amplitude of the first excitatory postsynaptic potential (EPSP) generated by rested synaptic pairs; (b) the time course and level of homosynaptic depression as revealed by delivery of 40 intracellular stimuli evoking presynaptic action potentials at 0.05 Hz; and (c), the extent to which a single bath application of 10 μM 5-Hydroxytryptamine creatinine sulfate complex (5HT) induced facilitation of the depressed synapse
Summary
Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as the accumulation of extracellular amyloid-β plaques, intra-neuronal neurofibrillary tangles formed by aberrantly phosphorylated tau, degeneration of neurites or neuronal loss (Terry et al, 1991; Arriagada et al, 1992; Selkoe, 2002; Coleman and Yao, 2003; Giannakopoulos et al, 2003; Saul et al, 2013). Using transgenic (Tg) mice exhibiting tau-induced cognitive decline, a number of studies have indicated that loss of dendritic spine or depletion of synaptic proteins appear prior to hallmark pathologies (Eckermann et al, 2007; Yoshiyama et al, 2007; Mocanu et al, 2008; Polydoro et al, 2009; Bittner et al, 2010; Hoover et al, 2010; Rocher et al, 2010; Crimins et al, 2011; Sydow et al, 2011a,b; Alldred et al, 2012; Spires-Jones and Knafo, 2012; Kopeikina et al, 2013).
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