P2Y₁₂ deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory

Abstract

Purinergic receptor P2Y (P2Y ), a G protein-coupled purinergic receptor, is widely distributed in nervous system and involved in the progression of neurological diseases such as multiple sclerosis and neuropathic pain. The central noradrenergic system actively participates in a number of neurophysiological processes. Nevertheless, whether there is any direct relevance between P2Y and noradrenergic signal transduction remains unknown. In the present study, we tested the hypothesis that lack of P2Y impaired noradrenergic signal transduction in mouse brain. Our results showed that P2Y knockout (KO) mice exhibited increased anxiety-like behavior in the open-field test (OFT) and elevated plus maze test and displayed deficits in memory in the radial-arm maze test (RAMT) and Morris water maze test (MWMT). They also exhibited reduced locomotion in the OFT and MWMT. Moreover, loss of P2Y decreased the level of noradrenaline and the expression of noradrenergic α receptors, subtypes α2 (ARα2b) in mouse cerebellum and hippocampus. Meanwhile, it hampered the protein kinase A (PKA)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway in these brain regions. Taken together, our results showed for the first time that P2Y KO altered the anxiety, memory and locomotion of mice, which was closely associated with abnormal state of noradrenergic system in the brain. The findings implicate that P2Y plays an indispensable role in noradrenergic signal transduction; its deficit is insufficient to limit anxiety responses or supports cognitive performance and activity.

Loss of P2Y12 Has Behavioral Effects in the Adult Mouse

“…In these experiments, we showed that unlike ocular dominance plasticity in the adolescent visual cortex, P2Y12 is not required for synaptic remodeling in the early development of the LGN, a process that is known to depend on microglia, nor is it required for microglial distribution within developing barrels in the somatosensory cortex. However, in line with previous investigations [25,26], the loss of P2Y12 results in altered behavior in the adult mouse, including increased anxiety, decreased social interactions, and more heterogeneous effects on learning. This suggests that loss of P2Y12 alters neural circuits and impacts adult brain function.…”

“…Several studies have reported changes in animal behavior after the disruption of microglial pathways that contribute to synapse remodeling [27][28][29]. Recently, a pair of studies examined the role of P2Y12 in fear acquisition and anxiety-like behaviors, finding that P2Y12 is required for innate fear learning and its loss increases anxiety-like behaviors [25,26]. In line with these results, we found enhanced anxiety-like behaviors in P2Y12 −/− mice as measured by FST, underscoring the function of P2Y12 in mediating anxiety responses.…”

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

“…The OFT was administrated as described previously [46]. In brief, the mice were individually placed into the center of an open box apparatus (50 cm × 50 cm × 40 cm) with a black floor.…”

Astragaloside IV enhances memory and modulates hippocampal synaptic plasticity by decreasing GABAergic inhibition through EGR-1 mediated BDNF/TrkB signaling pathway in mice

“…It was made of opaque plexiglass with manually operated doors lead from the hub of the central maze to each arm. RAMT was conducted in accordance with the procedure described previously, with minor modi cation [27]. As shown in Fig.…”