Microtubule Stabilizer Ameliorates Synaptic Function and Behavior in a Mouse Model for Schizophrenia

Abstract

A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia.

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

“…BMS-241027 reduced MT hyperdynamicity in rTg4510 mice to baseline levels BMS-241027, a brain-penetrant MT stabilizer with a long half-life in brain and a short half-life in blood (Andrieux et al, 2006;Brunden et al, 2010), was administered to rTg4510 mice. BMS-241027 has previously been used to reduce tumor formation in nude mice with 15-35 mg/kg, i.p., treatment every other day for five cycles for a cumulative dose of 75-175 mg/kg over 10 d (Kolman, 2004).…”

The microtubule-stabilizing drug Epothilone D increases axonal sprouting following transection injury in vitro

“…We have demonstrated that cortical neurons take approximately 2 weeks to mature to the stage where they form complex neuronal networks with multiple connections, fire action po- This study determined the role that Epo D manipulation of microtubule stabilization plays in regeneration. Epo D has been shown in vivo to promote polymerization of tubulin heterodimers into microtubules and stabilize pre-formed microtubules, and has recently generated interest as a potential candidate for protection from neurodegeneration (Brunden et al, , 2011Andrieux et al, 2006;Barten et al, 2012;Cartelli et al, 2013). However, Epo D is most commonly used as a drug in cancer therapy (Wang et al, 2005b), where it exerts it action by binding to tubulin and causing a microtubule-mediated obstruction of mitosis and cell division, producing an arrest of cell growth or apoptosis (Cheng et al, 2008;Cortes and Baselga, 2007).…”

“…However Epo D, a microtubule-stabilizing drug that competes with Paclitaxel for the binding site on β-tubulin (Brunden et al, 2011), may be an excellent alternative. Epo D readily crosses the BBB and is retained within the CNS for several days (Brunden et al, 2012;Andrieux et al, 2006;Wang et al, 2005a;Cortes and Baselga, 2007). It has been administered to mice carrying genetic mutations associated with familial Alzheimer's disease and other related tauopathies, and was shown to compensate for the loss of tau function, improve axonal transport, reduce axonal dystrophy, decrease tau neuropathology, reduce neuronal loss and improve cognitive performance Barten et al, 2012;Lou et al, 2014).…”

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

“…Of particular relevance for the current study, knock out mice for KIF1A and KIF1B have reduced numbers of synaptic vesicles, indicating that our finding of decreased synaptophysin mRNA expression, and reductions in the number of synaptic vesicles in STOP mutant mice (Andrieux et al, 2002), may be caused by altered KIF function and diminished transport (and thence synthesis) of synaptic vesicles. The finding that treatment of STOP null mice with the microtubule stabilizing drug epothilone D partially returns to normal synaptic vesicle density (Andrieux et al, 2006) supports a role for microtubule stabilization in synaptic vesicle transport, and it will be interesting to determine if synaptophysin mRNA expression is likewise increased…”