Reduced brain‐derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice

Abstract

Brain-derived neurotrophic factor (BDNF) regulates monoamine neuronal growth, survival and function in development and throughout adulthood. At 18 months of age, mice with constitutive reductions in BDNF expression show decreased serotonin innervation in the hippocampus compared with age-matched wildtype mice. It is not known, however, whether age-accelerated loss of serotonergic innervation in BDNF 1/2 mice occurs in other brain regions, advances beyond 18 months or is associated with alterations in other neurotransmitter systems. In this study, immunocytochemistry was used to assess serotonergic and catecholaminergic innervation in 26-month-old BDNF 1/2 mice. Age-related loss of serotonin axons in the hippocampus was potentiated in BDNF 1/2 mice compared with wildtype mice at this late age, particularly in the CA1 subregion. By contrast, aging BDNF 1/2 mice showed increased serotonin innervation of the basomedial nucleus of the amygdala. In the noradrenergic system, BDNF 1/2 mice showed reduced numbers of cell bodies and fibers in the locus coeruleus compared with age-matched wildtype mice, whereas no changes were observed in dopaminergic innervation with respect to genotype. In vivo zero net flux microdialysis in awake mice showed a significant decrease in extracellular serotonin levels in the hippocampus in BDNF 1/2 mice at 20 months of age. Thus, reduced BDNF is associated with altered serotonergic and noradrenergic innervation in aging mice and, in particular, with accelerated loss of serotonergic innervation to the hippocampus that is manifest as a decrease in basal neurotransmission.

Physiologically Relevant Changes in Serotonin Resolved by Fast Microdialysis

“…45 Faster Online Microdialysis for Serotonin (and Dopamine). By optimizing analysis conditions, we have reduced our detection threshold for serotonin from ∼5 32,34 to 0.8 fmol ( Figure 1A,B). Simultaneously, we decreased the retention time for serotonin from 17−20 min 32,34 to ∼2 min ( Figure 1C).…”

“…By optimizing analysis conditions, we have reduced our detection threshold for serotonin from ∼5 32,34 to 0.8 fmol ( Figure 1A,B). Simultaneously, we decreased the retention time for serotonin from 17−20 min 32,34 to ∼2 min ( Figure 1C). Using similar analysis conditions, both dopamine and serotonin were resolved with retention times of 1.2 and 2.6 Taking advantage of decreased retention times and increased sensitivity, we developed a tandem online injection setup that allowed a single HPLC instrument to analyze samples from two subjects simultaneously and in an automated manner.…”

“…At a collection rate of 20 min per sample, only 5−6 data points can be obtained in a 90 min serotonin infusion, and the overall R 2 value was ∼0.90. 32,34 The R 2 value was improved (>0.99) when the first 6 h (ZT2:30−8:30 for 4 concentrations) or the last 6 h (ZT5:30− 11:30 for 4 concentrations) were analyzed separately. This could be due to subtle circadian shifts in basal serotonin levels during the light phase ( Figure 4, dark gray bar A).…”

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

“…However, BDNF elevations with AMPH treatment could also be related to drug-induced increases of 5-HT and DA. Monoaminergic activity, which is elevated with AMPH, has been found to enhance the expression of BDNF (Fumagalli et al, 2003;Mattson et al, 2004;Miklic et al, 2004;Juric et al, 2006;Luellen et al, 2007). A third putative mechanism for AMPH to increase BDNF is through the cocaine-and amphetamine-regulated transcript (CART).…”

Contributions of impaired hippocampal plasticity and neurodegeneration to age-related deficits in hormonal pulsatility

“…Changes in levels of several different neurotransmitter and/or their receptors have been reported including: decreased levels of acetylcholine and decreased sensitivity of muscarinic receptors to acetylcholine (Lippa et al, 1982;Perry et al, 1993); alterations in levels of NMDA and AMPA glutamate receptors (Shi et al, 2007); and decreased serotonergic input to the hippocampus (Luellen et al, 2007). In addition, neurotrophic support of hippocampal neurons may be diminished during aging as suggested by a decline in the expression of brain-derived neurotrophic factor (BDNF) (Adlard et al, 2005;Luellen et al, 2007) and insulin-like growth factor 1 (IGF-1) (Sonntag et al, 1999). In addition to changes in various signaling pathways in neurons, there are age-related alterations in glial cells that modify plasticity and functions of the hippocampus.…”