Behavioral and neurochemical profile of MK-801 adult zebrafish model: Forebrain β2-adrenoceptors contribute to social withdrawal and anxiety-like behavior
Panagiotis Perdikaris, Catherine R. Dermon
Abstract
Deficits in social communication and interaction are core clinical symptoms characterizing multiple neuropsychiatric conditions, including autism spectrum disorder (ASD) and schizophrenia. Interestingly, elevated anxiety levels are a common comorbid psychopathology characterizing individuals with aberrant social behavior. Despite recent progress, the underlying neurobiological mechanisms that link anxiety with social withdrawal remain poorly understood. The present study developed a zebrafish pharmacological model displaying social withdrawal behavior, following a 3-h exposure to 4 μΜ (+)-MK-801, a non–competitive N-methyl-d-aspartate (NMDA) receptor antagonist, for 7 days. Interestingly, MK-801-treated zebrafish displayed elevated anxiety levels along with higher frequency of stereotypical behaviors, rendering this zebrafish model appropriate to unravel a possible link of catecholaminergic and ASD–like phenotypes. MK-801-treated zebrafish showed increased telencephalic protein expression of metabotropic glutamate 5 receptor (mGluR5), dopamine transporter (DAT) and β2–adrenergic receptors (β2-ARs), supporting the presence of excitation/inhibition imbalance along with altered dopaminergic and noradrenergic activity. Interestingly, β2-ARs expression, was differentially regulated across the Social Decision-Making (SDM) network nodes, exhibiting increased levels in ventral telencephalic area (Vv), a key-area integrating reward and social circuits but decreased expression in dorso-medial telencephalic area (Dm) and anterior tuberal nucleus (ATN). Moreover, the co-localization of β2-ARs with elements of GABAergic and glutamatergic systems, as well as with GAP-43, a protein indicating increased brain plasticity potential, support the key-role of β2-ARs in the MK-801 zebrafish social dysfunctions. Our results highlight the importance of the catecholaminergic neurotransmission in the manifestation of ASD–like behavior, representing a site of potential interventions for amelioration of ASD-like symptoms.