Abstract
Cortical gamma oscillations are believed to be involved in mental processes which are disturbed in schizophrenia. For example, the magnitudes of sensory-evoked oscillations, as measured by auditory steady-state responses (ASSRs) at 40 Hz, are robustly diminished, whereas the baseline gamma power is enhanced in schizophrenia. Such dual gamma oscillation abnormalities are also present in a mouse model of N-methyl-D-aspartate receptor hypofunction (Ppp1r2cre/Grin1 knockout mice). However, it is unclear whether the abnormal gamma oscillations are associated with dysfunction in schizophrenia. We found that glycogen synthase kinase-3 (GSK3) is overactivated in corticolimbic parvalbumin-positive GABAergic interneurons in Grin1 mutant mice. Here we addressed whether GSK3β inhibition reverses both abnormal gamma oscillations and behavioral deficits with high correlation by pharmacological and genetic approach. We demonstrated that the paralog selective-GSK3β inhibitor, but not GSK3α inhibitor, normalizes the diminished ASSRs, excessive baseline gamma power, and deficits in spatial working memory and prepulse inhibition (PPI) of acoustic startle in Grin1 mutant mice. Cell-type specific GSK3B knockdown, but not GSK3A knockdown, also reversed abnormal gamma oscillations and behavioral deficits. Moreover, GSK3B knockdown, but not GSK3A knockdown, reverses the mutants’ in vivo spike synchrony deficits. Finally, ex vivo patch-clamp recording from pairs of neighboring cortical pyramidal neurons showed a reduction of synchronous spontaneous inhibitory-postsynaptic-current events in mutants, which was reversed by GSK3β inhibition genetically and pharmacologically. Together, GSK3β inhibition in corticolimbic interneurons ameliorates the deficits in spatial working memory and PPI, presumably by restoration of synchronous GABA release, synchronous spike firing, and evoked-gamma power increase with lowered baseline power.
Highlights
The disturbance of neural oscillations in the gamma frequency band (30–100 Hz) is considered to be a core pathophysiological feature of schizophrenia, in the generation of cognitive dysfunction [1, 2]
Over-activation of glycogen synthase kinase-3 (GSK3) in cortical Grin1-deleted PV-positive neurons To explore whether GSK3 is up-regulated in the Grin1 mutant mice, we measured fluorescence intensity of auditory cortical neurons produced by fluorescent-labeled antibodies against GSK3α, GSK3β, and phospho-GSK3, an auto-activated form of GSK3 [31, 32], respectively (Fig. 1)
We demonstrated that GSK3β inhibition restores the in vivo cortical gamma oscillation and cognitive function in the mouse model of Grin1 hypofunction relevant to schizophrenia
Summary
The disturbance of neural oscillations in the gamma frequency band (30–100 Hz) is considered to be a core pathophysiological feature of schizophrenia, in the generation of cognitive dysfunction [1, 2]. In addition to impairment in evoked gamma oscillations, spontaneous or baseline gamma-band cortical activity during the resting state is reported in schizophrenia [6,7,8]. Genetic Grin deletion selectively from PV neurons in awake mice resulted in increased baseline gamma power [18, 19] and impaired optogenetically evoked-gamma oscillations [19], suggesting that Grin1-deleted PV neurons play a role in abnormal gamma oscillations. It remains to be Received: 1 February 2020 Revised: 27 July 2020 Accepted: 11 August 2020 Published online: 28 August 2020
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