Sex-specific effects of social isolation stress and ketamine on hippocampal plasticity

Abstract

Chronic social isolation stress (SIS) induces lasting negative effects on the brain, including memory deficits, cognitive impairments, and mood alterations such as depression and anxiety. All these symptoms, at least in part, reflect reduced hippocampal function. In both clinical and preclinical studies, subanesthetic doses of the NMDA receptor antagonist, ketamine (KET), was shown to have rapid and lasting antidepressant effects. Animal studies have shown that biological sex and levels of gonadal hormones alter the behavioral effects of KET, with ovarian hormones increasing sensitivity to the antidepressant-like effects of KET. Since the hippocampus plays a key role in mediating some of the effects of SIS, and considering that KET at low doses has been shown to rescue some of the behavioral deficits of isolation rearing this study aimed to assess the effects of isolation stress on pre- and post-synaptic hippocampal functions in male and female rats reared in SIS, as well as determine whether some of the physiological deficits can be rescued with a single injection of sub-anesthetic doses of KET. To do this, Sprague-Dawley rats were raised from weaning in either social isolation or with same-sex cage mate for 5 to 7 weeks. Male and female rats in either diestrus of proestrus received a single injection of KET (0, 2.5, or 5.0 mg/kg) three hours prior to termination and collection of acute hippocampal slices for ex vivo electrophysiological field potential recordings. Long-term potentiation (LTP) and paired pulse facilitation (PPF) outputs were assessed in a canonical CA3-CA1 dorsal hippocampal circuit. Our data show that SIS inhibits hippocampal LTP without affecting PPF in male rats, an effect that was rescued by KET. In female rats, isolation stress did not alter LTP, but did reduce PPF - especially when females were tested in diestrus-, an effect that was rescued by KET at the highest dose. Our data thus suggest sex differences in the contribution of pre-and postsynaptic hippocampal compartments in response to stress and KET.

Keywords: Estrous cycle; Hippocampus; Ketamine; Long term potentiation; Paired pulse facilitation; Plasticity; Sex differences; Social isolation.