Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity

Abstract

Abstract-This study was designed to identify molecular mechanisms by which exercise affects synaptic-plasticity in the hippocampus, a brain area whose function, learning and memory, depends on this capability. We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synapticplasticity. In fact, this impact of exercise is exemplified by our finding that BDNF regulates the mRNA levels of two end products important for neural function, i.e. cAMP-responseelement binding (CREB) protein and synapsin I. CREB and synapsin I have the ability to modify neuronal function by regulating gene-transcription and affecting synaptic transmission, respectively. Furthermore, we show that BDNF is capable of concurrently increasing the mRNA levels of both itself and its tyrosine kinaseB (TrkB) receptor, suggesting that exercise may employ a feedback loop to augment the effects of BDNF on synaptic-plasticity. The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that although BDNF mediates exerciseinduced hippocampal plasticity, additional molecules, i.e. the N-methyl-D-aspartate receptor, calcium/calmodulin protein kinase II and the mitogen-activated protein kinase cascade, modulate its effects. Since these molecules have a well-described association to BDNF action, our results illustrate a basic mechanism through which exercise may promote synaptic-plasticity in the adult brain.

Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats

“…The time length for exercise was based on previous studies indicating increases in BDNF and synapsin I after 7 days of voluntary exercise (Vaynman et al, 2003;Griesbach et al, 2004bGriesbach et al, , 2007. Rats had ad libitum access to food and water and were maintained on a 12-h light/dark cycle.…”

“…Pumps and drug concentration were chosen to infuse (to rats weighing on average 285 g) 1 mg/kg/day of AMPH or 1.0 μl/h of the vehicle (S) over 7 days. This drug administration method was chosen since our prior studies of RW exposure after TBI have left animals undisturbed for the 1 week exercise period (Vaynman et al, 2003;Griesbach et al, 2004bGriesbach et al, , 2007. The dose was chosen based on the recent report that 1 mg/kg/day of AMPH combined with rehabilitation training facilitates recovery after ischemic brain injury (Adkins and Jones, 2005).…”

Exercise decreases myelin‐associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

“…Infusion of TrkB-IgGs was achieved by coupling them to microbeads (Lumaflour Corp., Naples, FL), which we have previously used as a reservoir for the successful delivery of viable inhibitors into the hippocampus (Vaynman et al, 2003). Microbeads were coated via passive absorbency by incubating overnight at 4°C with a 1:5 mix of microbeads to TrkB-IgG 5 μg/μL in PBS with BSA, (Croll et al, 1998) or Cytochrome C (CytC) 100 ng/μL in sterile water (Lom and Cohen-Cory, 1999;Riddle et al, 1997).…”

The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function

“…Our previous efforts have identified the importance of the serine/threonine kinase calcium/ calmodulin protein kinase II (CAMKII) in mediating exercise-induced plasticity in the hippocampus, an area involved in learning and memory formation (Vaynman et al, 2003). Hippocampal CAMKII may likely contribute to perpetuating the effects of exercise on cognitive function.…”

“…Characteristically, exercise has been found to significantly increase BDNF, in the hippocampal area (Neeper et al, 1995;Vaynman et al, 2003), which has been shown to exhibit an abundant expression of the receptor (TrKB receptor) through which BDNF exerts its action (Maisonpierre et al, 1990;Murer et al, 2001). BDNF was initially consigned as a protein regulating the survival, growth, and differentiation of neurons during development (Barde, 1994), but it has become recognized as a critical modulator of synaptic-plasticity in the adult brain (Lo, 1995).…”