Abstract
Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity to ketamine. As accumulating evidence on molecular mechanisms and behavioral phenotypes established Sp4 hypomorphism as a promising animal model, systems-level neural circuit mechanisms of Sp4 hypomorphism, especially network dynamics underlying cognitive functions, remain poorly understood. We attempted to close this gap in knowledge in the present study by recording multi-channel epidural electroencephalogram (EEG) from awake behaving wildtype and Sp4 hypomorphic mice. We characterized cortical theta-band power and phase-coupling phenotypes, a known neural circuit substrate underlying cognitive functions, and further studied the effects of a subanesthetic dosage of ketamine on theta abnormalities unique to Sp4 hypomorphism. Sp4 hypomorphic mice had markedly elevated theta power localized frontally and parietally, a more pronounced theta phase progression along the neuraxis, and a stronger frontal-parietal theta coupling. Acute subanesthetic ketamine did not affect theta power in wildtype animals but significantly reduced it in Sp4 hypomorphic mice, nearly completely neutralizing their excessive frontal/parietal theta power. Ketamine did not significantly alter cortical theta phase progression in either wildtype or Sp4 hypomorphic animals, but significantly strengthened cortical theta phase-coupling in wildtype, but not in Sp4 hypomorphic animals. Our results suggested that the resting-state phenotypes of cortical theta oscillations unique to Sp4 hypomorphic mice closely mimicked a schizophrenic endophenotype. Further, ketamine independently modulated Sp4 hypomorphic anomalies in theta power and phase-coupling, suggesting separate underlying neural circuit mechanisms.
Highlights
SP4, a transcription factor targeting GC-rich sequences around the promoters of numerous genes [1], was found to be associated with schizophrenia, bipolar disorder and major depression [2,3,4,5]
A non-competitive NMDAR antagonist, is known to induce schizophrenia-like behavioral phenotypes in healthy subjects and exacerbate symptoms in patients [17,18,19,20], which is in line with the findings that patients with anti-NMDAR encephalitis developed schizophrenia-like cognitive symptoms [21,22]
Using a novel multi-channel epidural EEG technique [38], here we, for the first time, quantified cortical theta power and phase-coupling phenotypes associated with Sp4 hypomorphism in a systematic manner
Summary
SP4, a transcription factor targeting GC-rich sequences around the promoters of numerous genes [1], was found to be associated with schizophrenia, bipolar disorder and major depression [2,3,4,5]. SP4 gene was reported to be sporadically deleted in schizophrenia patients [6,7] and had reduced expression in postmortem brains of bipolar patients [8]. Sp4 hypomorphic mice had reduced NMDAR1 expression throughout the brain [7,12] consistent with postmortem analysis of schizophrenic brains [13,14,15], and displayed a host of behavioral phenotypes endophenotypic of schizophrenia and other psychiatric disorders [7,10,11,16], including deficit in prepulse inhibition (PPI) [10] and, as we recently reported, hypersensitivity to ketamine [16]. Consistent with the hypoglutamatergic hypothesis that schizophrenia is associated with impaired NMDA transmission, the Sp4 hypomorphic mouse presents a compelling animal model of the disorder in that it uniquely aggregates multiple validities: genetic (a risk gene), neurochemical (NMDAR hypofunction), behavioral (PPI deficits, etc.) and pharmacological (ketamine hypersensitivity)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
