The Glycine Transport Inhibitor Bi 425809 Restores Translatable EEG Deficits in an Acute Mouse Model for Schizophrenia-Related Sensory Processing and Cortical Network Dysfunction

AbstractAnimal models reflecting human risk for schizophrenia are essential research tools for gaining further insight into the convergence of CNS pathology and clinical biomarkers. Amongst the variety of animal models that display schizophrenia-related neuronal network deficits, transgenic mice for rare and highly penetrant copy number variants (CNVs) provide a unique opportunity to study pathological correlates in models with strong construct validity. The Df(h15q13)/+ mouse model of the human 15q13.3 microdeletion CNV has been shown to mimic deficits in parvalbumin positive (PV+) interneuron and cortical network function. However, the corresponding changes in synapse density and activity within the medial prefrontal cortex (mPFC) have not been described. Using high-content immunofluorescence imaging, we have shown a reduced density of PV+ neurons and inhibitory synapses in the mPFC of Df(h15q13)/+ mice. We found that the reduced detection of PV+ synapses were accompanied by changes in spontaneous inhibitory and excitatory synaptic activity onto layer 2/3 pyramidal neurons. The aberrant cortical function was also evident in awake animals by a reduced high frequency auditory steady-state responses (ASSR), reliably monitored by EEG. Importantly, the imbalance of excitatory to inhibitory function could be attenuated on a cellular and cortical network level by activation of mGlu2/3 receptors, indicating the relevance of excessive excitatory transmission to the cortical network deficit in the Df(15q13)/+ mouse model. Our findings highlight the preclinical value of genetic risk and in particular CNV models such as the Df(15q13)/+ mice to investigate pathological network correlates of schizophrenia risk and to probe therapeutic opportunities based on clinically relevant biomarkers.

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The glycine transport inhibitor sarcosine is an inhibitory glycine receptor agonist

Neuropharmacology ◽

10.1016/j.neuropharm.2009.07.019 ◽

2009 ◽

Vol 57 (5-6) ◽

pp. 551-555 ◽

Cited By ~ 22

Author(s):

Hai Xia Zhang ◽

Ariel Lyons-Warren ◽

Liu Lin Thio

Keyword(s):

Receptor Agonist ◽

Glycine Receptor ◽

Transport Inhibitor ◽

Glycine Transport

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M181. DEVELOPMENTAL PROGRESSION OF INTERNEURON NETWORK DEFICITS IN A 15Q13.3 MICRODELETION MOUSE MODEL – A GLIMPSE ON ADOLESCENT PRIMING FOR SCHIZOPHRENIA?

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.493 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S205-S205

Author(s):

Marzieh Funk ◽

Stefan Jaeger ◽

Niklas Schülert ◽

Cornelia Dorner-Ciossek ◽

Holger Rosenbrock ◽

...

Keyword(s):

Prefrontal Cortex ◽

Mouse Model ◽

Critical Period ◽

Neurodevelopmental Disorder ◽

Brain Slices ◽

Cortical Network ◽

Wild Type ◽

Perineuronal Net ◽

Network Function ◽

Adult Mice

Abstract Background Schizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthood Methods Immunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures. Results We initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenia-linked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice. Discussion In this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention.

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The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine

The Journal of Physiology ◽

10.1113/jphysiol.2009.168757 ◽

2009 ◽

Vol 587 (13) ◽

pp. 3207-3220 ◽

Cited By ~ 33

Author(s):

Hai Xia Zhang ◽

Krzysztof Hyrc ◽

Liu Lin Thio

Keyword(s):

Nmda Receptor ◽

Transport Inhibitor ◽

Glycine Transport

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Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome

Cerebral Cortex ◽

10.1093/cercor/bhz141 ◽

2019 ◽

Vol 30 (3) ◽

pp. 969-988 ◽

Cited By ~ 12

Author(s):

Jonathan W Lovelace ◽

Maham Rais ◽

Arnold R Palacios ◽

Xinghao S Shuai ◽

Steven Bishay ◽

...

Keyword(s):

Mouse Model ◽

Auditory Cortex ◽

Fragile X Syndrome ◽

Sensory Processing ◽

Fragile X ◽

Autism Spectrum ◽

Behavioral Phenotypes ◽

Excitatory Neurons ◽

Gamma Power ◽

Processing Deficits

Abstract Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.

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Systematic analysis of goal-related movement sequences during maternal behavior in a female mouse model for Rett syndrome

10.1101/2020.12.21.423671 ◽

2020 ◽

Author(s):

Parker K. Stevenson ◽

Devin M. Casenhiser ◽

Keerthi Krishnan

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Sensory Processing ◽

Female Mouse ◽

Learning Approaches ◽

Dynamic Changes ◽

Systematic Analysis ◽

Pup Retrieval ◽

First Time ◽

Day By Day

Parenting is an ethologically relevant social behavior consisting of stereotypic components involving the care and nourishment of young. First-time rodent dams seek and gather wandering/scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Over the decades, qualitative observations of the behaving animal have been presented in quantitative discrete units. However, systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioral sequence, which would be ultimately essential for understanding the underlying neurobiology, is usually not analyzed. Here, we present systematic analysis of pup retrieval behavior across three days in alloparental female mice (Surrogates or Sur) of two genotypes; Mecp2Heterozygotes (Het), a female mouse model for a neuropsychiatric disorder called Rett syndrome and their wild type (WT) siblings. Additionally, we analyzed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software.We previously showed that Het are inefficient, by measuring latency and errors, at pup retrieval. Here, we show that the sequence of searching, pup-approach and good retrieval crystallizes over time for WT; this sequence does not crystallize in Het. We found that goal-related movements of Het in different phases were similar to WT, suggesting context-driven atypical dynamic patterns in Het. We also identified pup approach and pup grooming as atypical tactile interactions between pups and Het, which contribute to inefficient pup retrieval. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains in response to the growing pups. Overall, our approach 1) embraces natural variation in individual mice on different days of pup retrieval behavior, 2) establishes a “gold-standard” manually curated dataset to next build behavioral repertoires using machine learning approaches, and 3) identifies distinct atypical tactile sensory processing in a female mouse model for Rett syndrome.

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