Increased Neurotransmitter Release at the Neuromuscular Junction in a Mouse Model of Polyglutamine Disease

Abstract

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice). We have found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-␣, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats.

Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum

“…It is also possible that the massive loss of huntingtin from corticostriatal terminals in the Emx-htt KO mice accounts for the phenotype. Huntingtin has been reported to associate with synaptic vesicles and facilitate neurotransmitter release in pre-synaptic excitatory synaptic terminals (DiFiglia et al, 1995; Rozas et al, 2011). If the huntingtin depletion preferentially diminished neurotransmitter release from cortical terminals ending on indirect pathway neurons, for example those of the pyramidal tract type corticostriatal neurons (Deng et al, 2015), hyperactivity would be the predicted outcome (Albin et al, 1989).…”

Synaptic Protein Alterations in Parkinson’s Disease

“…Use of a Drosophila HD model reported enhanced neurotransmitter release, resulting in neurodegeneration in neuromuscular synapses expressing mutant htt [21]. However, in order to discern primary synaptic changes from changes resulting from neurodegeneration, Rozas and colleagues [22] made use of a transgenic mouse model of HD to show that expanded htt increases synaptic release at vertebrate motor nerve terminals.…”

Decreased O-Linked GlcNAcylation Protects from Cytotoxicity Mediated by Huntingtin Exon1 Protein Fragment

“…The wild-type huntingtin protein plays important roles in normal functioning of the brain such as vesicular transport, neuronal gene transcription, and BDNF production (14) and may also function as an anti-apoptotic protein (15). The mHtt aggregates interfere with normal synaptic transmission (16), impair axonal transport of mitochondria (17), sequester crucial transcription factors (18), and hamper their functioning.…”