Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration

Abstract

We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4–6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH-DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18–24 months) throughout the forebrain by SERT immunohistochemistry and [3H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2 +) neurons within the dorsal raphe, as measured by unbiased stereology at 26–30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons.

Vesicular monoamine transporter 2 mediates fear behavior in mice

“…Our laboratory and others have previously demonstrated that VMAT2‐LO mice show decreased extracellular dopamine and norepinephrine concentrations compared with those measured in wild‐type mice . VMAT2‐LO mice also display decreased serotonergic transmission . Conversely, VMAT2‐HI mice show an increased capacity to store and release monoamines, particularly dopamine .…”

“…Primary outcome measure was peak dopamine release, which was evaluating by calculating the maximum current and dividing it by the calibration constant for that electrode. Measuring peak dopamine release is a common practice to determine stimulated neurotransmitter release . ANOVA with post hoc Dunnett's tests were performed to determine differences in peak stimulated dopamine release between genotypes.…”

Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain

“…Importantly, VMAT2 gene-dose has been linked to either neurotoxic or neuroprotective effects within each of the monoamine neurotransmitter systems including serotoninergic signaling (Alter et al, 2016), noradrenergic degeneration (Taylor et al, 2014), non-motor symptoms of PD (Taylor et al, 2009), and dopamine handling, toxicity, and dopamine-related neurodegeneration (Little et al, 2003; Lohr et al, 2015; Pifl et al, 2014). The significant expression of VMAT2 in dopaminergic regions such as the striatum and midbrain suggests possible sites of action for the previously reported VMAT2-mediated neuroprotection from toxic exposure to pesticides (Richardson et al, 2006), methamphetamine (Guillot et al, 2008; Lohr et al, 2015; Takahashi et al, 1997), and MPTP (Liu et al, 1992; Lohr et al, 2014).…”

“…Similarly, VMAT2-LO mice show neurodegeneration of the locus coeruleus (Taylor et al, 2014), a region that also degenerates in PD and shows immunoreactivity to our VMAT2 antibody. This observed reduction in immunoreactivity for VMAT2 in the VMAT2-LO mice is responsible for the disrupted serotonin signaling in these animals (Alter et al, 2016). These effects provide evidence that VMAT2 is broadly important in monoaminergic transmission, with higher gene-dose consistently linked to neuroprotection and lower gene-dose consistently linked to neurodegeneration and neuronal vulnerability.…”

Preliminary Evidence of Apathetic-Like Behavior in Aged Vesicular Monoamine Transporter 2 Deficient Mice

“…In VMAT2 LO mice norepinephrine concentrations are also drastically reduced, illustrated by progressive degeneration in the locus coeruleus, that even preceded degeneration in the substantia nigra pars compacta (Taylor et al, 2014). A recent study revealed that at the age of 4–6 months VMAT2 LO mice also exhibited dramatically reduced serotonin release capacity (Alter et al, 2015). Thus, reducing the VMAT2 LO model primary to a dopaminergic deficiency is oversimplifying, and the same criticism can be applied to the hypothesis of apathy being mainly caused by dopaminergic dysfunction.…”