NAAG peptidase inhibitors block cognitive deficit induced by MK-801 and motor activation induced by d-amphetamine in animal models of schizophrenia

Abstract

The most widely validated animal models of the positive, negative and cognitive symptoms of schizophrenia involve administration of d-amphetamine or the open channel NMDA receptor blockers, dizocilpine (MK-801), phencyclidine (PCP) and ketamine. The drug ZJ43 potently inhibits glutamate carboxypeptidase II (GCPII), an enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate (NAAG) and reduces positive and negative behaviors induced by PCP in several of these models. NAAG is an agonist at the metabotropic glutamate receptor 3 (mGluR3). Polymorphisms in this receptor have been associated with expression of schizophrenia. This study aimed to determine whether two different NAAG peptidase inhibitors are effective in dopamine models, whether their efficacy was eliminated in GCPII knockout mice and whether the efficacy of these inhibitors extended to MK-801-induced cognitive deficits as assessed using the novel object recognition test. ZJ43 blocked motor activation when given before or after d-amphetamine treatment. (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA), another potent NAAG peptidase inhibitor, also reduced motor activation induced by PCP or d-amphetamine. 2-PMPA was not effective in GCPII knockout mice. ZJ43 and 2-PMPA also blocked MK-801-induced deficits in novel object recognition when given before, but not after, the acquisition trial. The group II mGluR antagonist LY341495 blocked the effects of NAAG peptidase inhibition in these studies. 2-PMPA was more potent than ZJ43 in a test of NAAG peptidase inhibition in vivo. By bridging the dopamine and glutamate theories of schizophrenia with two structurally different NAAG peptidase inhibitors and demonstrating their efficacy in blocking MK-801-induced memory deficits, these data advance the concept that NAAG peptidase inhibition represents a potentially novel antipsychotic therapy.

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

“…To further demonstrate that pharmacological inhibition of STEP was sufficient to ameliorate the behavioral effects arising from NMDAR antagonism, we used another NMDAR blocker, MK-801, which has been widely validated as a pharmacological model of SZ and induces motor and cognitive deficits in mice 39-41 . In agreement with previous reports 42, 43 , we found MK-801 treatment induced hyperactivity (SI Figure 11a-c) and memory deficits in the Y-maze and novel object recognition tasks (SI Figure 11d, e); these deficits were significantly reversed by pretreatment with TC-2153 (SI Figure 11a-e).…”

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

“…Post-mortem studies in schizophrenia report alterations in NAAG (Reynolds and Reynolds, 2011; Ghose et al, 2009), indicating that NAAG may play a pivotal role in the pathophysiology of schizophrenia. Additional evidence stems from studies utilizing the PCP drug model of schizophrenia revealing that NAAG peptidase inhibitors prevent the behavioral and physiological effects of NMDA receptor antagonism in rodents (Olszewski et al, 2008; Olszewski et al, 2012; Zuo et al, 2012). …”

NAAG peptidase inhibitors and deletion of NAAG peptidase gene enhance memory in novel object recognition test

“…Inhibitors of glutamate carboxypeptidase II (GCPII), the enzyme that inactivates NAAG, elevate extracellular levels of the peptide and increase activation of this receptor (Adedoyin et al, 2010; Slusher et al, 1999; Zhong et al, 2006; Zuo et al, 2012). NAAG peptidase inhibitors are effective in animal models of several clinical conditions (Neale et al, 2005; 2011; Thomas et al, 2006; Wozniak et al, 2012) and rescue short-term memory impairment induced by a low dose of dizocilpine (MK801) (Olszewski et al, 2012b). This latter result suggested that these inhibitors also might affect learning or memory in mice in which cognition had not been artificially diminished.…”