Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia

Abstract

It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.

Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects

“…Moreover, an increasing body of evidence has suggested that Sp4 transcription factor has a role in complex psychotic disorders through its regulation of a large network of genes, including components of NMDAR signaling pathways (Fuste et al, 2013; Ji et al, 2013; Pinacho et al, 2011; Pinacho et al, 2013; Sun et al, 2015; Zhou et al, 2005). Notably, we also observed reduced SP4 protein abundance without changes in its mRNA expression in the cerebellum of schizophrenia subjects and in peripheral blood mononuclear cells from first-episode psychosis patients (Fuste et al, 2013; Pinacho et al, 2013).…”

“…Sp4 has been shown to be important for a variety of physiological processes in neurons, including dendrite outgrowth, the regulation of NMDA receptors, and long-term potentiation (Ji et al, 2013; Liu et al, 2003; Priya et al, 2013; Ramos et al, 2007; Ramos et al, 2009; Zhou et al, 2005; Zhou et al, 2010). It is unclear if changes in SP4 phosphorylation and levels represent an adaptive response to an upstream deficit, or if these changes contribute directly to the pathology of BD and SZ.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…After breeding the Sp4 Hyp mice with Cre lines, the LacZ gene can be deleted by the Cre to restore Sp4 gene expression. All test mice were the F1 generation mice with the same genetic background (Ji et al, 2013;Zhou et al, 2010), were 3 months old at the time of testing, and weighed between 21 and 28 g. All animals were group housed (maximum four/cage) and maintained in a temperature-controlled vivarium (21 ± 1°C) with a reversed 12 h day/night cycle (lights off at 0700 h and on at 1900 h). During training, mice were food restricted to maintain weight at 85% of their free-feeding weight, as is commonly used during reward-learning training (Young et al, 2011).…”

“…Reducing Sp4 expression (hypomorphic (Hyp)) in mice results in abnormalities relevant to schizophrenia and bipolar patients, eg, reduced sensorimotor gating (Zhou et al, 2005) and reduced N-methyl-D-aspartate receptor (NMDAR) protein expression . These mice are also hypersensitive to the NMDAR noncompetitive antagonist ketamine and competitive NMDAR antagonist SDZ 220-581, resulting in reduced habituation to a novel environment (Ji et al, 2013). Interestingly, acutely ill schizophrenia patients exhibit reduced habituation to a novel environment (Perry et al, 2009).…”

Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning

“…We have reported reduced Sp4 protein abundance in cerebellum and cerebral cortex of subjects with bipolar disorder and associated with severe negative symptoms in patients with schizophrenia (Pinacho et al, ; Pinacho et al, ). Mice with reduced expression of Sp4 have deficits in contextual and spatial memory, reduced LTP and increased sensitivity to the noncompetitive NMDAR antagonist, ketamine (Zhou et al, ; Zhou et al, ; Ji et al, ). Interestingly, Sp4 hypomorphic mice have reduced levels of NR1 protein, but not mRNA, which may contribute to some of these phenotypes (Zhou et al, ).…”