Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults

Abstract

In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.

Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors

“…Although early studies reported increased locomotor activity in mice expressing 5% of normal levels of GluN1 22 , recent investigation showed that locomotor activity in these mice is comparable to the locomotor activity of wild-type littermates in a familiar environment 57 . In fact, locomotor activity is not directly correlated to the levels of GluN1, as increased locomotor activity has been reported to be associated with both increase 58 or decrease 59 of GluN1 levels. PCP is often used to model aspects of schizophrenia, inducing their prominent psychotomimetic effects by blocking neurotransmission at NMDAR-type glutamate receptors and inducing schizophrenia-related behaviors 16 , 60 – 64 .…”

Role of cholesterol and sphingolipids in brain development and neurological diseases

“…A subtype of glutamate receptors named N-methyl-D-aspartate receptors (NMDARs), which mediates excitatory neuronal transmission, plays a critical role in brain functions [68]. Neurological and psychiatric disorders such as stroke, schizophrenia and certain forms of autism can be attributed to dysfunctional NMDARs [69, 70]. The 24S-hydroxycholesterol, a brain cholesterol metabolite, is a positive modulator of NMDARs when administered exogenously [71, 72].…”

Distributed sensory coding by cerebellar complex spikes in units of cortical segments

“…Immunohistochemistry was performed according to the method described elsewhere (Yasuda et al, 2017). Mouse monoclonal antibody against calbindin D28k (#300) was purchased from Swant and rabbit polyclonal antibody against GFP (MBL598) was purchased from MBL.…”