Abstract
It has been repeatedly shown that chronic stress changes dendrites, spines and modulates expression of synaptic molecules. These effects all may impair information transfer between neurons. The present study shows that chronic stress also regulates expression of M6a, a glycoprotein which is localised in axonal membranes. We have previously demonstrated that M6a is a component of glutamatergic axons. The present data reveal that it is the splice variant M6a-Ib, not M6a-Ia, which is strongly expressed in the brain. Chronic stress in male rats (3 weeks daily restraint) has regional effects: quantitative in situ hybridization demonstrated that M6a-Ib mRNA in dentate gyrus granule neurons and in CA3 pyramidal neurons is downregulated, whereas M6a-Ib mRNA in the medial prefrontal cortex is upregulated by chronic stress. This is the first study showing that expression of an axonal membrane molecule is differentially affected by stress in a region-dependent manner. Therefore, one may speculate that diminished expression of the glycoprotein in the hippocampus leads to altered output in the corresponding cortical projection areas. Enhanced M6a-Ib expression in the medial prefrontal cortex (in areas prelimbic and infralimbic cortex) might be interpreted as a compensatory mechanism in response to changes in axonal projections from the hippocampus. Our findings provide evidence that in addition to alterations in dendrites and spines chronic stress also changes the integrity of axons and may thus impair information transfer even between distant brain regions.
Highlights
The membrane glycoprotein M6a is the only member of the proteolipid protein family of tetraspan proteins to be expressed exclusively by neurons in the central nervous system [1,2]
M6a splice variants Ia and Ib A comparative real-time RT-PCR analysis of M6a transcript expression was performed in the brain and kidneys using primers specific for M6a isoforms Ia and Ib, and for the 39-UTR region of the M6a transcript which is common to both isoforms (Fig. 1A)
The results indicate that N-terminus variants of M6a are differentially expressed in central and peripheral tissues
Summary
The membrane glycoprotein M6a is the only member of the proteolipid protein family of tetraspan proteins to be expressed exclusively by neurons in the central nervous system [1,2]. Neuronal M6a was formerly suspected to play a role in the formation of nerve cell processes since in cultured cerebellar neurons treated with monoclonal M6a antibody, neurite formation was severely impaired [4]. Targeted depletion of endogenous M6a expression with small inhibitory RNA (siRNA) attenuated neurite outgrowth and impaired synapse formation [5]. Overexpression of M6a in cultured primary hippocampal neurons promoted neurite outgrowth and the formation of filopodial protrusions [5]. In a previous publication we showed that the membrane glycoprotein is not present in dendrites, but only in axons of glutamatergic neurons [6]. We analyzed the relative abundance of M6a splice variants Ia and Ib in the rat brain and their regulation by chronic stress exposure
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