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. 2020 Nov 15:179:108277.
doi: 10.1016/j.neuropharm.2020.108277. Epub 2020 Aug 18.

PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex

Erin P McEachern  1 , Austin A Coley  1 , Sha-Sha Yang  1 , Wen-Jun Gao  2
Affiliations

PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex

Erin P McEachern et al. Neuropharmacology. .

Abstract

Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95+/-), we studied how PSD-95 deficiency affects GABAA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABAA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95+/- mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.

Keywords: GABA receptors; Inhibitory transmission; PSD-95; Prefrontal cortex; Schizophrenia.

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Conflict of interest statement

Conflict of Interests

The authors report no competing interests or biomedical financial interests.

Figures

Figure 1.
Figure 1.. PSD-95 deficiency increases GABAaR α1 subunit expression.
(A) Representative Western blots are shown for PSD-95, GABAA α1, GABAA α2 and Gephyrin at postnatal day 35 for control and PSD-95+/− mice; normalized to actin. (B) Quantitative analysis of protein levels for PSD-95 (p=0.003, CON, n=4, PSD-95+/−, n=6), GABAA α1 (p=0.038, CON, n=5, PSD-95+/−, n=7), GABAA α2 (p=0.204, CON, n=4, PSD-95+/−, n=7) and Gephyrin (p=0.023, CON, n=4, PSD-95+/−, n=7). *p<0.05, **p<0.01.
Figure 2.
Figure 2.. PSD-95 increases inhibitory response in mPFC.
(A) Representative traces of sIPSCs recorded at −70mV, in the presence of DNQX from control and PSD-95+/− mice at postnatal day 40. (B, C) Summary histograms of sIPSC frequency ± s.e.m (p=0.00002; CON, n=12; PSD-95+/−, n=13), peak amplitude ± s.e.m (p=0.0031; CON, n=12; PSD-95+/−, n=13) and decay ± s.e.m (p=0.000006; CON, n=12; PSD-95+/−, n=13). *p<0.05, **p<0.01, ***p<0.001.
Figure 3.
Figure 3.. PSD-95 deficiency decreases E/I balance in mPFC.
(A) Representative traces of evoked EPSCs recorded at −60mV and IPSCs at 0mV in the presence of CPP from control and PSD-95 +/− mice at postnatal day 40. (B-D) Summary histograms of AMPAR-EPSC peak amplitude ± s.e.m ( p=0.103;CON, n=10; PSD-95+/−, n=12), GABAR-IPSC peak amplitude ± s.e.m (p=0.046; CON, n=10; PSD-95+/−, n=12) and EPSC/IPSC ratios measured ± s.e.m (p=0.001; CON, n=10; PSD-95+/−, n=12). *p<0.05, **p<0.01.
Figure 4.
Figure 4.. PSD-95 deficiency increases Neuroligin 2 expression in mPFC.
(A) Representative Western blots are shown for Neuroligin 2, SynGap 1 and ErbB4 at postnatal day 40 for control and PSD-95+/− mice; normalized to actin. (B) Quantitative analysis of protein levels for Neuroligin 2 ± s.e.m (p=0.033, CON, n=6, PSD-95+/−, n=6), SynGap 1± s.e.m (p=0.337, CON, n=5, PSD-95+/−, n= 6) and ErbB4 ± s.e.m (p=0.755, CON, n=6, PSD-95+/−, n=7). ). *p<0.05.
Figure 5.
Figure 5.. PSD-95 deficiency decreases GSK3β-tyr216 phosphorylation.
(A) Representative Western blots are shown for GSK3β, pGSK3β tyr 216 and pGSK3β ser9 at postnatal day 40 for control and PSD-95+/− mice; normalized to total GSK3β protein levels. (B) Quantitative analysis of protein levels for total GSK3β ± s.e.m (p=0.688, CON, n=5, PSD-95+/−, n=4), pGSK3β tyr 216 ± s.e.m (p=0.029, CON, n=5, PSD-95+/−, n=5) and pGSK3β ser9± s.e.m (p=0.267, CON, n=5, PSD-95+/−, n=5). *p<0.05.
Figure 6.
Figure 6.. PSD-95 deficiency increases the gephyrin/Neuroligin 2 association and decreases PSD-95/Neuroligin 2 association.
(A) Representative Western blots are shown for gephyrin, PSD-95, and NR2A at postnatal day 40 for control and PSD-95+/− mice; normalized to Neuroligin 2. (B) Quantitative analysis of protein levels (n=5-6, *p<0.05).
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