Using single-cell mass spectrometry technology, Zhu et al. [1] recently revealed that a novel intra-neuronal glutamate (GLU) biosynthetic pathway contributes to sunlight ultraviolet (UV)-induced neurobehavioral effects. In the study, moderate UV exposure was found to increase blood levels of urocanic acid (UCA), which may cross the blood–brain barrier (BBB). Subsequently, UCA promotes GLU biosynthesis and release in various brain regions, including motor cortex and hippocampus. Strikingly, UV exposure improves motor learning and object recognition memory. The inhibitor against urocanase, an enzyme critical for the conversion of UCA to GLU, reverses the UV exposure-related neurological effects. Thus, the activation of UCA-GLU metabolic pathway mediates the process of UV-triggered neurobehavioral changes (Fig. 1).
The molecular mechanism of moderate UV-induced neurobehavioral changes Moderate UV exposure increases UCA in the skin and enters the blood, which may cross the BBB and enter the neurons. Subsequently, UCA promotes GLU biosynthesis and release in the motor cortex and hippocampus. Strikingly, the GLU release improves motor learning and object recognition memory. The inhibitor against urocanase, an enzyme critical for the conversion of UCA to GLU, reverses the UV-related neurological function. Thus, this finding suggests that the role of GLU biosynthetic pathway in UV-induced neurobehavioral condition, may contribute to neurodegenerative disorders.
Currently, moderate UV light is known to yield beneficial health care, such as vitamin D synthesis and blood pressure modulation [2]. UV light has been reported to affect neurological behaviors, such as mood, addiction, cognition, and memory [3]. Furthermore, UV light accelerates neuroendocrine effect, leading to immunosuppressive responses [4]. Thus, UV plays an essential role in the regulation of neuroedocrine-immune functions at the systemic level. However, the underlying mechanism, which mediates UV-induced neurological behaviors remains elusive. Of note, this finding provides compelling evidence to support the notion that moderate UV exposure activates the UCA-GLU biosynthetic pathway in the brain, thus enhancing motor learning and recognition memory [1].
GLU is the most abundant of excitatory neurotransmitter in the central nervous system. Mounting evidence indicates that GLU plays a significant role in neural progenitor cell proliferation, migration, differentiation, and survival in the developing brain [5]. More specifically, GLU synthesis is involved in a variety of neurological processes, such as synaptic plasticity, cognitive improvement, and neuronal development [6]. In mammals, UCA is an intermediate in the conversion of histidine to GLU. Previous studies have demonstrated that UV exposure modulates UCA in the peripheral system including blood, skin, and urine [7,8].
The study by Zhu et al. [1] first discovered that the blood UCA induced by UV exposure participates in the GLU biosynthesis crossing the BBB into the brain. This UV-activated GLU biosynthesis may result in its packaging into synaptic vesicles and its release at glutamatergic terminals, thus improving learning and memory. Surprisingly, the presence of GLU may be highly associated with brain development [9], but the precise functions of metabolites in UCA–GLU pathway in brain development warrant further investigation.
Neurodegenerative diseases, include Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by neuronal degradations, dysfunctions or death [10]. It is well established that GLU signaling in neurodegeneration may be involved in the development of neurodegenerative disorders [11]. In the APP/PS1 transgenic mice, the upregulation of GLU not only improves learning and memory, but also enhances the surviving neurons in hippocampus, suggesting that GLU metabolism ameliorates cognitive impairment in AD [12]. Moreover, HD is characterized by motor, cognitive, and psychiatric symptoms that are related to GLU signaling [13]. The abnormal GLU release may cause the loss of motor neurons and onset of ALS [14]. Altogether, their findings illustrated that GLU metabolic pathway is very essential for neurological pathogenesis, such as AD, HD, and ALS.
In summary, the findings of Zhu et al. [1] revealed a hitherto unexplored mechanism by which the intracellular UCA–GLU metabolic pathway in brain is involved in UV-initiated neurobehavioral functions, including improving learning and memory. Remarkably, the GLU biosynthetic pathway in the brain may contribute to the development of neurodegenerative disorders. In the future, various drugs targeting this new intra-neuronal GLU biosynthetic pathway may provide a potential therapeutic approach for neurodegenerative diseases.
