Acute ketamine enhances social behavior and dendritic plasticity in the amygdala by increasing BDNF, GAP43, and TRKB presence following excitotoxic neonatal ibotenic acid lesion.

Social isolation, a negative symptom of schizophrenia that responds poorly to available treatments, may be alleviated by a single low dose of ketamine. In a rat model mimicking schizophrenia-related social deficits through neonatal brain lesions, a single ketamine injection improved social behavior, increased the complexity of brain cell connections in the amygdala, and elevated levels of proteins linked to brain plasticity—BDNF, TRKB, and GAP43. The results suggest that acute sub-anesthetic ketamine could provide a temporary window to help individuals with schizophrenia engage with and continue treatment.

Study at a glance

Abstract

Schizophrenia is a highly disabling psychopathology that is a significant burden on public health systems and is characterized by both positive and negative symptoms. One of these negative symptoms is social isolation, which responds poorly to available treatments. Ketamine (KET) has been shown to enhance social behavior in various preclinical models, accompanied by neurobiological changes. In this study, we used a preclinical model of schizophrenia involving neonatal ventral hippocampal (NVHL) bilateral lesions induced by excitotoxicity with ibotenic acid (IA) at postnatal day 7 (PD). Thirty male Sprague-Dawley rats, aged 7 PD, were assigned to one of the following groups: Intact, Sham, Intact + KET, IA + Saline, and IA + KET, with n = 6 per group. Rats in the Sham, IA + Saline, and IA + KET groups underwent stereotaxic surgery and were administered with either 0.3 % saline or IA at 7 PD. At 35 PD, the rats received either saline or ketamine (15 mg/kg) and were assessed using the three-chamber social test. A Golgi-modified technique was then employed to evaluate neuronal changes in the amygdala with Sholl analysis. Also, immunohistochemistry was conducted to measure brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TRKB), and growth-associated protein 43 (GAP43). Acute KET treatment rescued social behavior, increased dendritic tree complexity, and elevated BDNF, TRKB, and GAP43 protein presence. Our results suggest that acute sub-anesthetic administration of KET may help alleviate social isolation symptoms. This dose could provide a window of opportunity to encourage individuals with schizophrenia to initiate and continue their treatment.