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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:Background: Neuropsychiatric symptoms due to Alzheimer's disease (AD) and mild cognitive impairment (MCI) can decrease quality of life for patients and increase caregiver burden. Better characterization of neuropsychiatric symptoms and methods of analysis are needed to identify effective treatment targets. The current investigation leveraged the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to examine the network structure of neuropsychiatric symptoms among symptomatic older adults with cognitive impairment. Methods: The network relationships of behavioral symptoms was estimated from Neuropsychiatric Inventory Questionnaire (NPI-Q) data acquired from 12,494 older adults with MCI and AD during their initial visit. Network analysis provides insight into the relationships among sets of symptoms and allows calculation of the strengths of the relationships. Nodes represented individual NPI-Q symptoms and edges represented the pairwise dependency between symptoms. Node centrality was calculated to determine the relative importance of each symptom in the network. Results: The analysis showed patterns of connectivity among the symptoms of the NPI-Q. The network ( M =.28) consisted of mostly positive edges. The strongest edges connected nodes within symptom domain. Disinhibition and agitation/aggression were the most central symptoms in the network. Depression/dysphoria was the most frequently endorsed symptom, but it was not central in the network. Conclusions: Neuropsychiatric symptoms in MCI and AD are highly comorbid and mutually reinforcing. The presence of disinhibition and agitation/aggression yielded a higher probability of additional neuropsychiatric symptoms. Interventions targeting these symptoms may lead to greater neuropsychiatric symptom improvement overall. Future work will compare neuropsychiatric symptom networks across dementia etiologies, informant relationships, and ethnic/racial groups, and will explore the utility of network analysis as a means of interrogating treatment effects.

Project description:BackgroundPrescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is scarce. Our objective was to describe the comparative safety of pharmacologic interventions for treating neuropsychiatric symptoms in dementia.MethodsWe searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, from inception to May 28, 2019, for studies of pharmacologic interventions used to treat neuropsychiatric symptoms in dementia. Dementia care partners selected fracture risk as our primary outcome. Pairs of reviewers, working independently, conducted all study screening, data abstraction, and risk of bias appraisal. We conducted Bayesian random-effects network meta-analyses (NMAs) using data from RCTs to derive odds ratios (ORs). In secondary analyses, we conducted frequentist random-effects NMAs using data from RCTs and Bayesian three-level hierarchical random-effects NMAs incorporating data from RCTs and non-randomized studies.ResultsOur systematic review included 209 randomized and non-randomized studies (889,378 persons with dementia). In NMAs of data from randomized trials, there were no increased odds of fracture associated with any intervention in primary analyses; however, data were sparse. We found increased odds of cerebrovascular events associated with antipsychotics (odds ratio [OR] 2.12, 95% credible interval [CrI] 1.29 to 3.62; number needed to harm [NNH] = 99) and increased odds of falls associated with dextromethorphan-quinidine (OR 4.16, 95% CrI 1.47 to 14.22; NNH = 55) compared to placebo in persons with dementia. In a subgroup of persons with Alzheimer disease, antipsychotics were associated with increased odds of fracture compared to anticonvulsants (OR 54.1, 95% CrI 1.15 to 38,300; NNH = 18). In older persons (mean age ≥ 80 years) with dementia, anticonvulsants were associated with increased odds of death compared to placebo (OR 8.36, 95% CrI 1.17 to 203.4; NNH = 35) and antipsychotics were associated with increased odds of death compared to antidepressants (OR 5.28, 95% CrI 1.06 to 3.51; NNH = 47).ConclusionAlthough antipsychotics were associated with greater harm than antidepressants and anticonvulsants in subgroups of persons with dementia, medications used in lieu of antipsychotics for treating neuropsychiatric symptoms in dementia, such as anticonvulsants and dextromethorphan-quinidine, were also associated with harm. Decision-making concerning treatments prescribed in lieu of antipsychotics should include potential harms.Prospero registrationCRD42017050130.

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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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