Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain

Abstract

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.

Ternary Cu(II) Complex with GHK Peptide and Cis-Urocanic Acid as a Potential Physiologically Functional Copper Chelate

“…GHK and UCA also are present in the blood, although at lower concentrations [ 8 ]. UCA crosses the blood–brain barrier and was even found in cerebrospinal fluid and neurons [ 9 ]. GHK was also found to be transported into the brain [ 6 ].…”

“…Urocanic acid (UCA) is a component of natural moisturizing factor (NMF) in the uppermost layer of the skin (stratum corneum) [ 7 ]. It is also found in blood [ 8 ] and neurons [ 9 ]. UCA is the product of histidine deamination by histidine ammonia–lyase (histidase).…”

“…Recently, it was found that UCA can cross the blood–brain barrier and be transported into neurons. Furthermore, histidase activity has also been found in neurons [ 9 ]. Importantly, there is a positive correlation between the content of histidine (the substrate for production of UCA) and wound healing [ 13 , 14 ].…”

Astrocytic Regulation of Glutamate Transmission in Schizophrenia

“…D-serine is converted from L-serine by the action of SR and is released by Ca 2+ -dependent and/or -independent machineries from astrocytes ( 19 , 37 ) [but see ( 38 )]. Notably, these above processes might interact with one another; for example, the increased glutamate synthesis leads to elevated glutamate release ( 39 ), and activation of glutamate transports could evoke rapid glutamine release as a feedback mechanism ( 40 ).…”

Sunlight Brightens Learning and Memory

“…In this issue of Cell, using a breadth of techniques ranging from single-cell metabolite analysis to electrophysiology and behavioral assays, Xiong and colleagues reveal a previously unknown mechanism by which sunlight may enhance learning and memory ( Figure 1) (Zhu et al, 2018). First, the authors take advantage of a unique single-cell metabolite profiling method developed by their group to interrogate the intracellular composition of neurons (Zhu et al, 2017).…”