Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Tan, Tao; Wang, Wei; Williams, Jamal B; Ma, Kaijie; Cao, Qing; Yan, Zhen

doi:10.1093/schbul/sby163

Cited by 19 publications

(16 citation statements)

References 65 publications

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“…Cell Article ll approach (SA) test (Tan et al, 2019) was performed during in vivo multichannel recordings of neuronal spike activity (Figure 2A). Compared with GH females, SI females exhibited significantly shorter interaction time with social stimuli (Figure 2B), suggesting the presence of social deficits.…”

Section: Resultsmentioning

confidence: 99%

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

et al. 2021

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Exposure to prolonged stress in critical developmental periods induces heightened vulnerability to psychiatric disorders, which may have sex-specific consequences. Here we investigate the neuronal circuits mediating behavioral changes in mice after chronic adolescent social isolation stress. Escalated aggression is exhibited in stressed males, while social withdrawal is shown in stressed females. In vivo multichannel recordings of free-moving animals indicate that pyramidal neurons in prefrontal cortex (PFC) from stressed males exhibit the significantly decreased spike activity during aggressive attacks, while PFC pyramidal neurons from stressed females show a blunted increase of discharge rates during sociability tests. Chemogenetic and electrophysiological evidence shows that PFC hypofunctioning and BLA principal neuron hyperactivity contribute to the elevated aggression in stressed males, while PFC hypofunctioning and VTA dopamine neuron hypoactivity contribute to the diminished sociability in stressed females. These results establish a framework for understanding the circuit and physiological mechanisms underlying sex-specific divergent effects of stress.

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Section: Resultsmentioning

confidence: 99%

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

et al. 2021

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“…A pipette puller (Model P‐97, Sutter Instrument Co.) was used to pull recording pipettes from glass capillaries (1.5 mm OD and 0.86 mm ID) with resistance at 3–5 MΩ. Whole‐cell voltage‐clamp recording was used to measure synaptic currents in PFC layer V pyramidal neurons (Tan et al, 2019 ; Wang et al, 2018 ). Pipette was filled with the intracellular solution (in mM: 130 Cs‐methanesulfonate, 10 CsCl, 4 NaCl, 1 MgCl 2 , 10 HEPES, 5 EGTA, 2 QX‐314, 12 phosphocreatine, 5 MgATP, 0.2 Na 3 GTP, 0.1 leupeptin, pH 7.3, 270 mOsm).…”

Section: Methodsmentioning

confidence: 99%

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

et al. 2021

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Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.

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“…All statistical analyses were performed with Graphpad Prism and Minitab 18. Sample sizes were determined based on power analyses and were similar to those reported in previous works ( 36 ). Experiments with more than two groups were subjected to one-way ANOVA, two-way ANOVA, or three-way ANOVA with Bonferroni correction for multiple post-hoc comparisons.…”

Section: Methodsmentioning

confidence: 99%

Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

et al. 2020

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The human 16p11.2 gene locus is a hot-spot for copy number variations which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2 dp/+ ) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2 dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity or motor impairment. Electrophysiological recordings of 16p11.2 dp/+ mice found the deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2 dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2 dp/+ mice ameliorated the social and cognitive deficits and reversed the GABAergic synaptic impairment and neuronal hyper-excitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

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Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Cited by 19 publications

References 65 publications

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

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