Abstract
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1ΔPV mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1ΔPVmice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.
Highlights
Schizophrenia is a common and debilitating disease with a wide spectrum of symptoms
The hypothesis that NMDAtype glutamate receptors (NMDARs) hypofunction on PV interneurons is at the core of the pathophysiology of schizophrenia has been advanced in multiple versions.[6,12,13,14]
Age–genotype interaction: P = 0.02, analysis of variance (ANOVA); we show that rather than being protected against the effects of MK-801 Grin1ΔPV mice are sensitized to its actions
Summary
Schizophrenia is a common and debilitating disease with a wide spectrum of symptoms. While positive symptoms such as hallucinations and delusions are central to its diagnosis, a large share of the disease burden results from negative and cognitive symptoms, such as social withdrawal, decreased motivation, and anhedonia, or deficits in working memory, attention and cognitive flexibility, respectively.[1]. We investigated the effects of MK-801 or vehicle injection in Grin1ΔPV mice and controls on the NMDARs in such neurons not cause reliable cognitive deficits and hyperlocomotion in the first place?15,17,18,20 Second, locomotor activity is a rather non-specific assay of behavior and its automated analysis via infrared beam-break counts may be accelerating rotarod test of motor coordination, spatial working memory (rewarded alternation on the elevated T-maze), a sucrose preference test of anhedonia and during in vivo recording of local field potentials in mPFC (see Supplementary Materials and Methods for full details). Studies of genetically modified mice in which NMDARs have been selectively ablated from principal cells in the forebrain have revealed robust hyperactivity, as well as deficits in tests of cognition that might be relevant to schizophrenia.[21,22,23,24,25,26,27,28,29]
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