Restoration of Sp4 in forebrain GABAergic neurons rescues hypersensitivity to ketamine in Sp4 hypomorphic mice

Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms were observed in schizophrenia patients after administration of ketamine. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Our previous studies found that Sp4 hypomorphic mice displayed several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. Here, we report differential genetic restoration of Sp4 expression in forebrain excitatory neurons or GABAergic neurons in Sp4 hypomorphic mice and the effects of these restorations on different behavioral phenotypes. Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating, fear learning, or ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating or fear learning. Our studies suggest that the Sp4 gene in forebrain GABAergic neurons plays an essential role in regulating some behavioral responses to ketamine.

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BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment

Translational Psychiatry ◽

10.1038/s41398-021-01365-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mahmoud Harb ◽

Justina Jagusch ◽

Archana Durairaja ◽

Thomas Endres ◽

Volkmar Leßmann ◽

...

Keyword(s):

Prepulse Inhibition ◽

Sensorimotor Gating ◽

Enriched Environment ◽

Fear Learning ◽

Set Shifting ◽

Wild Type ◽

Mature Adult ◽

Attentional Set ◽

Attentional Set Shifting ◽

The Brain

AbstractBrain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF’s role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/−) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/− mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/− mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/− mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

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Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons

eLife ◽

10.7554/elife.59799 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Anna J Bowen ◽

Jane Y Chen ◽

Y Waterlily Huang ◽

Nathan A Baertsch ◽

Sekun Park ◽

...

Keyword(s):

Basal Forebrain ◽

Behavioral Responses ◽

Freezing Behavior ◽

Fear Learning ◽

Autonomic Arousal ◽

Flexible Control ◽

Somatic Pain ◽

Unpredictable Environments ◽

Adaptive Processes ◽

Simultaneous Activation

Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses in mice, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRPPBN neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRPPBN neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning. Moreover, the unconditioned responses generated by individual projections are complementary, with simultaneous activation of multiple sites driving profound freezing behavior and bradycardia that are not elicited by any individual projection. This semi-parallel, scalable connectivity schema likely contributes to flexible control of threat responses in unpredictable environments.

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Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K+ channels primarily in excitatory neurons of the spinal dorsal horn

Journal of Neurophysiology ◽

10.1152/jn.01050.2010 ◽

2011 ◽

Vol 105 (6) ◽

pp. 3010-3021 ◽

Cited By ~ 29

Author(s):

Hui-Juan Hu ◽

Robert W. Gereau

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Neuronal Excitability ◽

Gabaergic Neurons ◽

Erk Signaling ◽

Metabotropic Glutamate ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Excitatory Neurons

Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

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Mechanisms of GABAergic Homeostatic Plasticity

Neural Plasticity ◽

10.1155/2011/489470 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 28

Author(s):

Peter Wenner

Keyword(s):

Gabaergic Neurons ◽

Homeostatic Plasticity ◽

Network Activity ◽

Gabaergic Inhibition ◽

Synaptic Connections ◽

Glutamatergic Synapses ◽

Cellular Excitability ◽

Excitatory Neurons ◽

Gabaergic Synapses ◽

Simplistic Model

Homeostatic plasticity ensures that appropriate levels of activity are maintained through compensatory adjustments in synaptic strength and cellular excitability. For instance, excitatory glutamatergic synapses are strengthened following activity blockade and weakened following increases in spiking activity. This form of plasticity has been described in a wide array of networks at several different stages of development, but most work and reviews have focussed on the excitatory inputs of excitatory neurons. Here we review homeostatic plasticity of GABAergic neurons and their synaptic connections. We propose a simplistic model for homeostatic plasticity of GABAergic components of the circuitry (GABAergic synapses onto excitatory neurons, excitatory connections onto GABAergic neurons, cellular excitability of GABAergic neurons): following chronic activity blockade there is a weakening of GABAergic inhibition, and following chronic increases in network activity there is a strengthening of GABAergic inhibition. Previous work on GABAergic homeostatic plasticity supports certain aspects of the model, but it is clear that the model cannot fully account for some results which do not appear to fit any simplistic rule. We consider potential reasons for these discrepancies.

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Electrocortical and behavioral responses elicited by acute electrical stimulation of inferior thalamic peduncle and nucleus reticularis thalami in a patient with major depression disorder

Clinical Neurophysiology ◽

10.1016/j.clinph.2005.10.023 ◽

2006 ◽

Vol 117 (2) ◽

pp. 320-327 ◽

Cited By ~ 27

Author(s):

Marcos Velasco ◽

Francisco Velasco ◽

Fiacro Jiménez ◽

José D. Carrillo-Ruiz ◽

Ana Luisa Velasco ◽

...

Keyword(s):

Electrical Stimulation ◽

Major Depression ◽

Behavioral Responses ◽

Major Depression Disorder ◽

Nucleus Reticularis ◽

Depression Disorder ◽

Stimulation Of

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3D Clustering of GABAergic Neurons Enhances Inhibitory Actions on Excitatory Neurons in the Mouse Visual Cortex

Cell Reports ◽

10.1016/j.celrep.2014.10.057 ◽

2014 ◽

Vol 9 (5) ◽

pp. 1896-1907 ◽

Cited By ~ 8

Author(s):

Teppei Ebina ◽

Kazuhiro Sohya ◽

Itaru Imayoshi ◽

Shu-Ting Yin ◽

Rui Kimura ◽

...

Keyword(s):

Visual Cortex ◽

Gabaergic Neurons ◽

Excitatory Neurons ◽

Mouse Visual Cortex

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GABAergic neurons in nucleus accumbens are correlated to resilience and vulnerability to chronic stress for major depression

Oncotarget ◽

10.18632/oncotarget.16411 ◽

2017 ◽

Vol 8 (22) ◽

pp. 35933-35945 ◽

Cited By ~ 26

Author(s):

Zhaoming Zhu ◽

Guangyan Wang ◽

Ke Ma ◽

Shan Cui ◽

Jin-Hui Wang

Keyword(s):

Nucleus Accumbens ◽

Major Depression ◽

Chronic Stress ◽

Gabaergic Neurons

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Chronic chemogenetic activation of forebrain excitatory neurons in postnatal life evokes long-lasting changes in mood-related behavior

10.1101/2020.02.19.956060 ◽

2020 ◽

Author(s):

Sthitapranjya Pati ◽

Kamal Saba ◽

Sonali S. Salvi ◽

Praachi Tiwari ◽

Pratik R. Chaudhari ◽

...

Keyword(s):

Sensorimotor Gating ◽

Behavioral Changes ◽

Early Adversity ◽

Postnatal Life ◽

Behavioral Alterations ◽

Excitatory Neurons ◽

History Of ◽

Anxiety Depression ◽

Activity Dependent ◽

Adult Psychopathology

AbstractEarly adversity is a key risk factor for the development of adult psychopathology, including anxiety, depression and schizophrenia. Rodent models of early adversity program persistent behavioral, molecular, metabolic, and neurophysiological changes. Perturbed signaling via forebrain Gq-coupled neurotransmitter receptors is a common feature across multiple models of early adversity. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke long-lasting mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of CamKIIα-positive forebrain excitatory neurons during postnatal life (P2-14) increased anxiety- and despair-like behavior, and evoked sensorimotor gating deficits in adulthood. In contrast, chronic chemogenetic hM3Dq DREADD activation of forebrain excitatory neurons in the juvenile or adult window did not evoke any mood-related behavioral alterations, highlighting the criticality of the postnatal temporal window. The enhanced anxiety-, despair- and schizophrenia-like behavioral changes evoked by chronic chemogenetic activation of forebrain excitatory neurons in postnatal life, was accompanied by an increased cortical and hippocampal metabolic rate of glutamatergic and GABAergic neurons in adulthood. Furthermore, animals with a history of postnatal hM3Dq activation exhibited a decline in the expression of activity-dependent and plasticity-associated markers within the hippocampus, along with perturbed hippocampal excitatory and inhibitory currents in adulthood. These results indicate that Gq signaling mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as metabolic and neurophysiological changes in forebrain glutamate and GABA systems, recapitulating specific aspects of the consequences of early adversity.

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Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior

eLife ◽

10.7554/elife.56171 ◽

2020 ◽

Vol 9 ◽

Author(s):

Sthitapranjya Pati ◽

Kamal Saba ◽

Sonali S Salvi ◽

Praachi Tiwari ◽

Pratik R Chaudhari ◽

...

Keyword(s):

Gabaergic Neurons ◽

Behavioral Changes ◽

Neurotransmitter Receptors ◽

Early Adversity ◽

Postnatal Life ◽

Rodent Models ◽

Functional Changes ◽

Excitatory Neurons ◽

Reduced Activity ◽

Adult Psychopathology

Early adversity is a risk factor for the development of adult psychopathology. Common across multiple rodent models of early adversity is increased signaling via forebrain Gq-coupled neurotransmitter receptors. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke persistent mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of forebrain excitatory neurons during postnatal life (P2–14), but not in juvenile or adult windows, increased anxiety-, despair-, and schizophrenia-like behavior in adulthood. This was accompanied by an enhanced metabolic rate of cortical and hippocampal glutamatergic and GABAergic neurons. Furthermore, we observed reduced activity and plasticity-associated marker expression, and perturbed excitatory/inhibitory currents in the hippocampus. These results indicate that Gq-signaling-mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as functional changes in forebrain glutamate and GABA systems, recapitulating aspects of the consequences of early adversity.

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