Photoperiod-induced neurotransmitter plasticity declines with aging: an epigenetic regulation?

Abstract

Neuroplasticity has classically been understood to arise through changes in synaptic strength or synaptic connectivity. A newly discovered form of neuroplasticity, neurotransmitter switching, involves changes in neurotransmitter identity. Chronic exposure to different photoperiods alters the number of dopamine (tyrosine hydroxylase, TH+) and somatostatin (SST+) neurons in the paraventricular nucleus (PaVN) of the hypothalamus of adult rats and results in discrete behavioral changes. Here we investigate whether photoperiod-induced neurotransmitter switching persists during aging and whether epigenetic mechanisms of histone acetylation and DNA methylation may contribute to this neurotransmitter plasticity. We show that this plasticity is robust at 1 and at 3 months but reduced in TH+ neurons at 12 months and completely abolished in both TH+ and SST+ neurons by 18 months. De novo methylation and histone 3 acetylation were observed following short-day photoperiod exposure in both TH+ and SST+ neurons at 1 and 3 months while an overall increase in methylation of SST+ neurons paralleled neuroplasticity reduction at 12 and 18 months. Histone acetylation increased in TH+ neurons and decreased in SST+ neurons following short-day exposure at 3 months while the total number of acetylated PaVN neurons remained constant. Reciprocal histone acetylation in TH+ and SST+ neurons suggests the importance of studying epigenetic regulation at the circuit level for identified cell phenotypes. The association of age-dependent reduction in neurotransmitter plasticity and changes in DNA methylation and acetylation patterns in two neuronal phenotypes known to switch transmitter identity suggests mechanistic insights into transmitter plasticity in the aging brain. SIGNIFICANCENeurotransmitter switching, like changes in synaptic strength, formation of new synapses and synapse remodeling, declines with age. This age-dependent reduction in transmitter plasticity is associated with changes in levels of DNA methylase and histone deacetylase that imply epigenetic regulation of transcription. A reciprocal pattern of histone acetylation in a single population of neurons that depends on the transmitter expressed emphasizes the value of studying epigenetic mechanisms at the level of cell phenotypes rather than cell genotypes or whole tissue. The findings may be useful for developing approaches for non-invasive treatment of disorders characterized by neurotransmitter dysfunction.