Subclass imbalance of parvalbumin-expressing GABAergic neurons in the hippocampus of a mouse ketamine model for schizophrenia, with reference to perineuronal nets

Abstract

Impairments of parvalbumin-expressing GABAergic neurons (PV⁺ neurons) and specialized extracellular structures called perineuronal nets (PNNs) have been found in schizophrenic patients. In this study, we examined potential alterations in four subclasses of PV⁺ neurons colocalized with PNNs in the hippocampus of a mouse ketamine model for schizophrenia. Because biosynthesis of human natural killer-1 (HNK-1) is shown to be associated with the risk of schizophrenia, here we used mouse monoclonal Cat-315 antibody, which recognizes HNK-1 glycans on PNNs. Once-daily intraperitoneal injections of ketamine for seven consecutive days induced hyper-locomotor activity in the open field tests. The prepulse inhibition (PPI) test showed that PPI scores declined in ketamine-treated mice compared to vehicle-treated mice. The densities of PV⁺ neurons and Cat-315⁺ PNNs declined in the CA1 region of ketamine-treated mice. Interestingly, the density of Cat-315⁺/PV⁺ neurons was lower in ketamine-treated mice than in vehicle-treated mice, whereas the density of Cat-315^-/PV⁺ neurons was not affected by ketamine. Among the four subclasses of PV⁺ neurons, the densities of Cat-315⁺/PV⁺ basket cells and Cat-315^-/PV⁺ axo-axonic cells were lower in ketamine-treated mice than in vehicle-treated mice, while the densities of Cat-315^-/PV⁺ basket cells and Cat-315⁺/PV⁺ axo-axonic cells were not affected by ketamine. Taken together, PNNs may not play a simple neuroprotective role against ketamine. Because different subclasses of PV⁺ neurons are considered to play distinct roles in the hippocampal neuronal network, the ketamine-induced subclass imbalance of PV⁺ neurons may result in abnormal network activity, which underlies the pathophysiology of schizophrenia.

Keywords: Cat-315 antibody; Hippocampus; Ketamine; Parvalbumin; Perineuronal net; Schizophrenia.