Loss of Phenotype of Parvalbumin Interneurons in Rat Prefrontal Cortex Is Involved in Antidepressant- and Propsychotic-Like Behaviors Following Acute and Repeated Ketamine Administration

Abstract

Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. To test this hypothesis, ketamine's antidepressant-like effects were evaluated by the forced swimming test. Ketamine-induced stereotyped behaviors and hyperactivity actions and the function of PV interneurons were also assessed. We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects. Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

“…This result was recapitulated by RT-qPCR ( Figure S8) and unsupervised WGCNA analysis where we detected PV+ interneuron-associated module ("green") with greater repression in aged post-stroke mice ( Figure 5). Dysfunction or loss of PV+ interneurons is implicated in the pathology of numerous neuropsychiatric disorders, including schizophrenia 116,117 , Alzheimer's disease 118 and depression 119,120 . Given their central role in the modulation of neuronal plasticity and cortical information processing 73,74,121,122 -processes that underlie recovery after stroke 123 -the PV+ interneurons may represent novel therapeutic target to promote functional recovery in elderly stroke patients.…”

Recent insights into the mode of action of memantine and ketamine

“…Similarly, memantine inhibition of NMDARs was proposed to produce cognitive improvements in AD patients through disinhibition [52], although memantine's ability to mediate disinhibition has not been directly assessed. Ketamine reduces expression of the important GABAergic interneuron markers parvalbumin (a Ca 2+ binding protein) and GAD67 (a GABA synthetic enzyme) in rodents, thereby compromising inhibitory neuron function [53-55]. The relation of decreased interneuron function to increased oscillations, however, has been questioned [56,57].…”

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

“…Abnormalities in PV interneurons are apparent in several neuropsychological diseases, including epilepsy [12], schizophrenia [13], Alzheimer's disease [14], and depression [15]. Disturbances in the functional maturation of PV interneurons during the peri-adolescent period may trigger the occurrence of schizophrenia, while maternal separation of male rats leads to a reduction of PV expression in the prefrontal cortex (PFC) and causes subsequent working memory impairments in adolescence [16].…”