Layer-specific axonal degeneration of serotonergic fibers in the prefrontal cortex of aged A53T α-synuclein–expressing mice

• Published in: Neurobiology of aging Vol. 80; pp. 29 - 37
• Main Authors: Wihan, Jeanette, Grosch, Janina, Kalinichenko, Liubov S., Müller, Christian P., Winkler, Jürgen, Kohl, Zacharias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2019
• Subjects: Aging - metabolism; Alpha-synuclein; alpha-Synuclein - metabolism; Animals; Axons - pathology; Disease Models, Animal; Mice; Nerve Degeneration; Parkinson Disease - pathology; Parkinson's disease; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Serotonergic Neurons - pathology; Serotonin; Serotonin transporter; Parkinson's disease; Serotonin transporter; Prefrontal cortex; Serotonin; Alpha-synuclein
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2019.03.014

Axonal pathology precedes dopaminergic cell loss in Parkinson's disease (PD), indicating a dying back axonopathy of nigrostriatal projections. Although most attention focused on the dopaminergic system, increasing evidence implies a compromised serotonergic system in PD as well. By combining immunohistological and biochemical approaches, a profound layer-specific reduction of the serotonergic input to the prefrontal cortex (PFC) layers II and V/VI in aged mutant A53T α-synuclein–expressing mice (A53T mice) was detected. In addition, the altered fiber network was characterized by swollen axons and enlarged axonal varicosities within all PFC layers, but most pronounced in PFC layer I. Although prefrontal serotonin levels and synaptic protein expression were preserved, aged A53T mice showed increased levels of kinesin family member 1a and vesicular monoamine transporter 2. Together with increased tryptophan hydroxylase 2 mRNA levels in the raphe nuclei and an elevated serotonin receptor 1b expression in the PFC, these findings point to compensatory mechanisms within the serotonergic system to overcome the reduced neuritic input to the PFC in this transgenic animal model for PD. •Aged A53T mice show a strong expression of α-syn in the prefrontal cortex (PFC).•Serotonergic innervation of PFC layers II and V/VI is reduced in A53T mice.•Prefrontal serotonergic fibers of A53T mice contain enlarged axonal varicosities.•Axonal degeneration is presumably compensated by increased 5-HT synthesis.•The PFC of A53T mice shows elevated levels of Rab3a, Kif1a, vMAT2, and 5-HT1b receptors.