Objectives: 

Synaptic transmission continually occurring at nerve terminals likely induces use-dependent waning of the molecular machinery involved in synaptic vesicle cycling. Interestingly, knock-out (KO) mice lacking the synaptic vesicle protein Cysteine String Protein-alpha (CSP-alpha) suffer from a presynaptic degeneration that is activity-dependent. For example, at the hippocampus of CSP-alpha KO mice , the terminals from high firing rate GABAergic basket cells preferentially degenerate in contrast to glutamatergic terminals with a lower action potential firing rate (García-Junco-Clemente et. al., JNeurosc. 30:7377-7391, (2010)). However, the molecular mechanisms responsible for presynaptic degeneration are not well known. Interestingly, mutations in DNAJC5, encoding CSP-alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis in humans (Nosková et al., Am J Hum Genet. 89:241-52 (2011)).

Materials: 

Here, we have investigated gene expression changes secondary to CSP-alpha genetic deletion at hippocampi isolated from CSP-alpha and control littermates at 20-24 days postnatal age. We have used two gene expression analysis methods to study transcriptional changes at the hippocampus of CSP-alpha KO mice: (a) Affymetrix Mouse Genome 430 2.0 Arrays for genome-wide expression analysis and (b) competitive PCR combined with MALDI-TOF mass spectroscopy analysis of PCR products (Sequenom).

Results: 

Both methods indicate an unexpected downregulated expression of several genes related to myelination in the hippocampus of CSP-alpha KO mice. Consistently, biochemical and electron microscopy analysis detect signs of progressive demyelination in CSP-alpha KO mice.

Conclusions: 

Future experiments will have to elucidate the unexpected relationship between the genetic removal of CSP-alpha, the dysregulation of myelination and the synaptic degeneration in CSP-alpha KO mice.