Anxiety Disorders: Zhuo M

Wu LJ, Kim SS, Zhuo M. · Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada. · Neurochem Res. · Pubmed #18386176 No free full text.

Abstract: Anxiety is a common human emotional experience that causes decreased quality of life and increased social burden worldwide. However, the treatment options currently available for anxiety are limited as the molecular mechanisms of these complicated emotional disorders are poorly understood. With the development of integrative methods including genetic manipulations, a variety of molecular targets involved in anxiety have been revealed, from membrane receptors, such as 5-HT receptor, GABA(A) receptor and GluR5 kainate receptor, and intracellular signaling proteins, such as CaMKIV and AC8, to transcription factors, such as CREB and Egr-1. We propose that all these molecules act together to form a balance between excitatory and inhibitory transmission that is critical for physiological anxiety, and that prolonged disturbance of any of them can promote pathological anxiety-like behavior. Studies on the interactions between these molecules will help elucidate the cellular mechanisms of anxiety, and will provide molecular targets for treating the disorders.

Creson TK, Hao Y, Engel S, Shen Y, Hamidi A, Zhuo M, Manji HK, Chen G. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD 20892-3711, USA. · Bipolar Disord. · Pubmed #19500087 No free full text.

Abstract: OBJECTIVES: Several intracellular signaling cascades, such as the extracellular signal-regulated kinase (ERK), Wnt-signaling/GSK-3, PLC/PKC, and PI3K pathways, have been shown to be affected directly or indirectly by mood stabilizers. Clinical imaging studies reveal that mood disorders are associated with structural and/or metabolic changes in specific brain regions such as the anterior cingulate cortex (ACC). Here we investigated the extent to which perturbation of one of the affected pathways, the ERK pathway, in the ACC influences affective-related behavior. METHODS: The regional perturbation was induced by two means: local continuous infusion of PD98059, an ERK pathway inhibitor, and microinjection of a lentiviral-mediated gene delivery system encoding functional negative ERK1. The outcomes were monitored with a battery of affective-related tests similar to those used in several previous studies. RESULTS: Compared to their respective controls, rats infused with PD98059 or injected with the lentiviral negative ERK1 construct displayed hyperactivities in multiple tests, exhibited preferentially more open-arm activity in the elevated-plus-maze test, consumed more sweetened liquid in a saccharin preference test, and showed heightened response to amphetamine. CONCLUSIONS: These data support a role for the ACC ERK pathway in the regulation of affective-related behaviors. However, the medial prefrontal cortex (mPFC) comprises at least three other regions that will need to be similarly examined before specific roles of the ACC ERK pathway can be definitively attributed to affective behaviors. Additionally, responses of other signaling pathways to mood stabilizers in these mPFC regions, as well as the limbic regions to which they project, will be important to examine.

Hines RM, Wu L, Hines DJ, Steenland H, Mansour S, Dahlhaus R, Singaraja RR, Cao X, Sammler E, Hormuzdi SG, Zhuo M, El-Husseini A. · Department of Psychiatry, Brain Research Centre, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · J Neurosci. · Pubmed #18550748 links to  free full text

Abstract: The level of excitation in the brain is kept under control through inhibitory signals mainly exerted by GABA neurons. However, the molecular machinery that regulates the balance between excitation and inhibition (E/I) remains unclear. Candidate molecules implicated in this process are neuroligin (NL) adhesion molecules, which are differentially enriched at either excitatory or inhibitory contacts. In this study, we use transgenic mouse models expressing NL1 or NL2 to examine whether enhanced expression of specific NLs results in synaptic imbalance and altered neuronal excitability and animal behavior. Our analysis reveals several abnormalities selectively manifested in transgenic mice with enhanced expression of NL2 but not NL1. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool in frontal cortex synapses and an overall reduction in the E/I ratio. The frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of transgenic NL2 mice. These animals also manifested stereotyped jumping behavior, anxiety, impaired social interactions, and enhanced incidence of spike-wave discharges, as depicted by EEG analysis in freely moving animals. These findings may provide the neural basis for E/I imbalance and altered behavior associated with neurodevelopmental disorders.

Du J, Creson TK, Wu LJ, Ren M, Gray NA, Falke C, Wei Y, Wang Y, Blumenthal R, Machado-Vieira R, Yuan P, Chen G, Zhuo M, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20878, USA. · J Neurosci. · Pubmed #18171924 links to  free full text

Abstract: The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.

Zhao MG, Toyoda H, Ko SW, Ding HK, Wu LJ, Zhuo M. · Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. · J Neurosci. · Pubmed #16093389 links to  free full text

Abstract: Trace fear memory requires the activity of the anterior cingulate cortex (ACC) and is sensitive to attention-distracting stimuli. Fragile X syndrome is the most common form of mental retardation with many patients exhibiting attention deficits. Previous studies in fragile X mental retardation 1 (FMR1) knock-out (KO) mice, a mouse model for fragile X, focused mainly on hippocampal-dependent plasticity and spatial memory. We demonstrate that FMR1 knock-out mice show a defect in trace fear memory without changes in locomotion, anxiety, and pain sensitivity. Whole-cell path-clamp recordings in the ACC show that long-term potentiation (LTP) was completely abolished. A similar decrease in LTP was found in the lateral amygdala, another structure implicated in fear memory. No significant changes were found in basal synaptic transmission. This suggests that synaptic plasticity in the ACC and amygdala of FMR1 KO mice plays an important role in the expression of behavioral phenotypes similar to the symptoms of fragile X syndrome.