Effects of aging on glutamate neurotransmission in the substantia nigra of Gdnf heterozygous mice

Abstract

Glial cell line-derived neurotrophic factor (GDNF) helps protect dopaminergic neurons in the nigrostriatal tract. Although the cause of nigrostriatal degeneration is unknown, one theory is that excess glutamate from the subthalamic nucleus (STN) results in excitotoxic events in the substantia nigra (SN). Since dopaminergic degeneration is accompanied by a reduction in GDNF, we examined glutamate neurotransmission in the SN using a Gdnf heterozygous mouse model (Gdnf+/−) at 8 and 12 months of age. At 8 months, Gdnf+/− mice have greater glutamate release and higher basal glutamate levels, which precede the SN dopaminergic degeneration observed at 12 months of age. However, at 12 months, Gdnf+/− mice have lower basal levels of glutamate and less glutamate release than wildtype (WT) mice. Also at 8 months, Gdnf+/− mice have lower levels of GLT-1 and greater GFAP levels in the SN compared to WT mice, differences that increase with age. These data suggest that reduced levels of GDNF induce excess glutamate release and dysregulation of GLT-1, causing excitotoxicity in the SN that precedes dopaminergic degeneration.

Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease

“…Initially, we looked at KCl-stimulated glutamate release in the dorsal striatum of MitoPark mice at 28 weeks of age, an age previously shown to develop LID in these mice (Shan et al, 2015). Glutamate release was measured by the amplitude of the electrochemical peak produced in response to pressure ejected 70 mM KCl (Farrand et al, 2015) which was applied locally in the dorsal striatum (Fig. 2B (dotted arrows) & 2C).…”

“…Additionally, we assessed the kinetics of glutamate uptake as it has been previously reported that excess glutamate in the synaptic cleft can result in excitotoxic events as a result of over-activation of post-synaptic receptors leading to cell death (Misonou et al, 2006). In this study we examined glutamate uptake by measuring k −1 (sec −1 ), a constant of the decay of glutamate clearance signals (Farrand et al, 2015). As can be seen in Fig.…”

“…Following baseline period, pressure ejections of 70 mM KCl solution were performed using the Picospritzer III microinjection dispensing system. Pressure ejection of 70 mM KCl (70 mM KCl, 79 mM NaCl, 2.5 mM CaCl 2 , pH 7.4) has been repeatedly shown to lead to a depolarization event and release of glutamate into the extra-cellular space, causing a robust and reproducible rise in the glutamate signal compared to baseline (Hascup et al, 2007; Hascup et al, 2012; Farrand et al, 2015). The maximum change in concentration compared to baseline is referred to as maximum amplitude or amplitude of the glutamate signal.…”

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

“…[95] suggest that reduced levels of GDNF induce excess glutamate release and deregulation of glutamate transporter-1, causing excitotoxicity in the nervous system that precedes dopaminergic degeneration. In this sense, a study performed by [96], showed GDNF expression level was increased with age in the frontal cortex, but was not in the hippocampus, in the agedependent changes in LC noradrenergic innervations suggesting that these innervations may be locally regulated by different neurotrophic factors that exert their trophic actions at different target sites.…”

Elevated glutamate and lactate predict brain death after severe head trauma

“…Notably, both of these neurotrophins modulate the activity of glutamatergic neurotransmission, which includes neuronal synaptic release and astrocytic glutamate uptake transporters activity/expression19, 20, while BDNF specifically modulates the expression of the high‐affinity monocarboxylate transporters 2 (MCT2) in neurons 21. The MCT2 controls the influx of energetic substrates including lactate to the oxidative metabolism in neurons 21.…”