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Changes in neural network homeostasis trigger neuropsychiatric symptoms.

ABSTRACT: The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.

SUBMITTER: Winkelmann A

PROVIDER: S-EPMC3904623 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Changes in neural network homeostasis trigger neuropsychiatric symptoms.

Winkelmann Aline A Maggio Nicola N Eller Joanna J Caliskan Gürsel G Semtner Marcus M Häussler Ute U Jüttner René R Dugladze Tamar T Smolinsky Birthe B Kowalczyk Sarah S Chronowska Ewa E Schwarz Günter G Rathjen Fritz G FG Rechavi Gideon G Haas Carola A CA Kulik Akos A Gloveli Tengis T Heinemann Uwe U Meier Jochen C JC

The Journal of clinical investigation 20140116 2

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain- ...[more]

PMID: 24430185

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Project description:Neuropsychiatric symptoms affect 37% of US adults and present in many important diagnoses including posttraumatic stress disorder, traumatic brain injury, and chronic pain. However, these symptoms are difficult to treat with standard treatments, and patients may seek alternative options. In this study, we examined the use of mind-body therapies by adults with neuropsychiatric symptoms.We compared mind-body therapy use (biofeedback, energy healing, meditation, guided imagery, yoga, deep-breathing exercises, hypnosis, progressive relaxation therapy, qigong, and tai chi) between adults with and without neuropsychiatric symptoms (anxiety, depression, insomnia, headaches, memory deficits, attention deficits, and excessive daytime sleepiness) in the 2007 National Health Interview Survey (N = 23,393). Use of ≥ 1 of these therapies in the prior 12 months was the primary outcome of interest. We also examined prevalence and reasons for mind-body therapy use in adults with neuropsychiatric symptoms. We performed logistic regression to examine the association between neuropsychiatric symptoms and mind-body therapy use to adjust for sociodemographic and clinical factors.Adults with ≥ 1 neuropsychiatric symptom used mind-body therapies more than adults without symptoms (25.3% vs 15.0%, P < .001). Prevalence increased with increasing number of symptoms (21.5% for 1 symptom, 32.4% for ≥ 3 symptoms, P < .001); differences persisted after adjustment for potential confounders (odds ratios, 1.39 [95% CI, 1.26-1.53] and 2.48 [95% CI, 2.18-2.82]). Reasons for mind-body therapy use among adults with ≥ 1 symptom included the ineffectiveness or expense of conventional medicine (30.2%). Most adults (nearly 70%) with ≥ 1 symptom did not discuss their mind-body therapy use with a conventional provider.Adults with ≥ 1 neuropsychiatric symptom use mind-body therapies frequently; more symptoms are associated with increased use. Future research is needed to understand the efficacy of these therapies.

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Changes in neural network homeostasis trigger neuropsychiatric symptoms.

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Changes in neural network homeostasis trigger neuropsychiatric symptoms.

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