Abstract
Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. Careful examination of NPS receptor (NPSR1) knockout mice at different ages revealed that PPI deficits are only expressed in young male knockout animals (<12 weeks of age), that can be replicated in NPS precursor knockout mice and appear strain-independent, but are absent in female mice. PPI deficits can be aggravated by MK-801 and alleviated by clozapine. Importantly, treatment of wildtype mice with a centrally-active NPSR1 antagonist was able to mimic PPI deficits. PPI impairment in young male NPSR1 and NPS knockout mice may be caused by attentional deficits that are enhanced by increasing interstimulus intervals. Our data reveal a substantial NPS-dependent developmental influence on PPI performance and confirm a significant role of attentional processes for sensory-motor gating. Through its influence on attention and arousal, NPS appears to positively modulate PPI in young animals, whereas compensatory mechanisms may alleviate NPS-dependent deficits in older mice.
Highlights
The neuropeptide S (NPS) system has received considerable attention as either a genetic risk factor or potential therapeutic target for several psychiatric disorders, including anxiety and schizophrenia
Since prepulse inhibition (PPI) deficits in schizophrenic patients as well as in pharmacologically-induced animal models can be reversed by treatment with the atypical antipsychotic clozapine, we studied the effect of clozapine (2 mg/kg i.p.) on PPI disruption in male C57Bl/6J-NPSR1
Such a model is consistent with reports that the low-functioning NPSR1-Asn107 variant was significantly associated with schizophrenia in a German cohort, in which decreased verbal memory consolidation was found in homozygous NPSR1-Asn107 carriers, who are predicted to possess attenuated NPS neurotransmission [18]
Summary
The neuropeptide S (NPS) system has received considerable attention as either a genetic risk factor or potential therapeutic target for several psychiatric disorders, including anxiety and schizophrenia. Behavioral and physiological effects of NPS have been investigated in several preclinical animal models of psychosis-related behaviors, and two genetic association studies have investigated a possible link between NPS receptor (NPSR1). Due to NPS-induced arousal-promoting effects, it was initially investigated for potential therapeutic effects in the most commonly used animal model in schizophrenia research, i.e., prepulse inhibition (PPI). Our group first reported ameliorating effects of central NPS administration on MK-801-induced pathological, neurochemical, and behavioral disruptions. NPS was shown to reverse MK-801-induced disruption of PPI and displayed a pharmacological profile similar to atypical antipsychotics [1]. Male NPSR1 knockout (KO) mice appeared to show no phenotypical changes in PPI performance, PPI levels were consistently—but
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