GSK3β inhibition restores cortical gamma oscillation and cognitive behavior in a mouse model of NMDA receptor hypofunction relevant to schizophrenia

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.

Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

“…Similarly, treatment with BRD3731, a selective GSK-3β inhibitor, normalized abnormal cortical gamma oscillations and reversed deficits in working memory and acoustic startle of prepulse inhibition (PPI) in mice carrying a hypofunctional NMDS (N-methyl-d-aspartate) receptor (Nakao et al, 2020). In confirmation, subsequent knockdown of GSK-3β in these mice also reversed these behavioral deficits (Nakao et al, 2020).…”

“…In mice carrying a microdeletion on chromosome 22q11.2, a mutation that accounts for about 1%-2% of sporadic schizophrenia (Tamura et al, 2016), treatment with SB-216763 at the postnatal stage, rescued deficits in neural synchrony, taskrelated neural activity, and spatial working memory (Tamura et al, 2016). Similarly, treatment with BRD3731, a selective GSK-3β inhibitor, normalized abnormal cortical gamma oscillations and reversed deficits in working memory and acoustic startle of prepulse inhibition (PPI) in mice carrying a hypofunctional NMDS (N-methyl-d-aspartate) receptor (Nakao et al, 2020). In confirmation, subsequent knockdown of GSK-3β in these mice also reversed these behavioral deficits (Nakao et al, 2020).…”

Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

“…Additionally, Nguyen et al [ 193 ] demonstrated that the inhibition of GSK-3 in rats, by a selective inhibitor or lithium, also influenced both theta and gamma band activity. GSK-3β inhibition in the corticolimbic interneurons of Ppp1r2-cre/floxed-Grin1 knockout mice has also been shown to both ameliorate deficits in spatial working memory and evoke gamma power increases in the primary auditory cortex [ 194 ]. Importantly, evidence suggests that reductions in 5-HT signaling, the main outcome of IDO’s metabolic process, may also influence neuronal system activity.…”

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

“…In the search of cortical excitability, we used in vivo local field potential (LFP) recording in awake animals, and applied periodic auditory steady-state response (ASSR) stimuli, comprised of 50 repetitions of 40-Hz click-trains with inter-stimulus interval (ISI) of 20 s. As previously reported [ 19 , 20 ], the Grin1 mutant mice show diminished ASSR oscillatory power following the N1 peak (the first negatively-evoked response). Here we found that N1 -like spontaneous LFP activities were frequently observed during ISIs in the Grin1 mutant mice, suggesting cortical hyperexcitability elicited by ASSR acoustic stimuli.…”