Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior

Abstract

Introduction: Deficits in social communication are in the core of clinical symptoms characterizing many neuropsychiatric disorders such as schizophrenia and autism spectrum disorder. The occurrence of anxiety-related behavior, a common co-morbid condition in individuals with impairments in social domain, suggests the presence of overlapping neurobiological mechanisms between these two pathologies. Dysregulated excitation/inhibition balance and excessive neuroinflammation, in specific neural circuits, are proposed as common etiological mechanisms implicated in both pathologies.

Methods and results: In the present study we evaluated changes in glutamatergic/GABAergic neurotransmission as well as the presence of neuroinflammation within the regions of the Social Decision-Making Network (SDMN) using a zebrafish model of NMDA receptor hypofunction, following sub-chronic MK-801 administration. MK-801-treated zebrafish are characterized by impaired social communication together with increased anxiety levels. At the molecular level, the behavioral phenotype was accompanied by increased mGluR5 and GAD67 but decreased PSD-95 protein expression levels in telencephalon and midbrain. In parallel, MK-801-treated zebrafish exhibited altered endocannabinoid signaling as indicated by the upregulation of cannabinoid receptor 1 (CB1R) in the telencephalon. Interestingly, glutamatergic dysfunction was positively correlated with social withdrawal behavior whereas defective GABAergic and endocannabinoid activity were positively associated with anxiety-like behavior. Moreover, neuronal and astrocytic IL-1β expression was increased in regions of the SDMN, supporting the role of neuroinflammatory responses in the manifestation of MK-801 behavioral phenotype. Colocalization of interleukin-1β (IL-1β) with β₂-adrenergic receptors (β₂-ARs) underlies the possible influence of noradrenergic neurotransmission to increased IL-1β expression in comorbidity between social deficits and elevated anxiety comorbidity.

Discussion: Overall, our results indicate the contribution of altered excitatory and inhibitory synaptic transmission as well as excessive neuroinflammatory responses in the manifestation of social deficits and anxiety-like behavior of MK-801-treated fish, identifying possible novel targets for amelioration of these symptoms.

Keywords: GABAergic; NMDAR hypofunction; anxiety; endocannabinoid system; glutamatergic neurotransmission; neuroinflammation; social deficits.