Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex.

Abstract

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.

• Authors: Rose Temizer, Yi-Wen Chen, Chiye Aoki
• Journal: Synapse (New York, N.Y.) (Synapse) Vol. 77 Issue 1 Pg. e22253 (01 2023) ISSN: 1098-2396 [Electronic] United States
• PMID: 36121749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• drebrins
• Ketamine
• gamma-Aminobutyric Acid

Topics

• Mice
• Female
• Animals
• Ketamine (pharmacology)
• Anorexia Nervosa (drug therapy, metabolism)
• Anorexia (drug therapy, metabolism)
• Individuality
• Synapses (metabolism)
• Disease Models, Animal
• Prefrontal Cortex (metabolism)
• Cytoplasm (metabolism)
• gamma-Aminobutyric Acid (metabolism)