Nrg1 haploinsufficiency alters inhibitory cortical circuits

Navarro-González, Carmen; Carceller, Héctor; Vicente, Marina Benito; Serra, Irene; Navarrete, Marta; Domínguez-Canterla, Yaiza; Rodríguez-Prieto, Ángela; González-Manteiga, Ana; Fazzari, Pietro

doi:10.1016/j.nbd.2021.105442

Cited by 13 publications

(16 citation statements)

References 70 publications

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“…One week after CCD, the brains were collected and processed in floating coronal sections, equidistantly distributed in the series. The injury volume was obtained by measuring the area of each affected slice [ 20 ]. In young mice, the average volume of the CCD was 1.26 ± 0.13 mm 3 ( Figure 3 C).…”

Section: Resultsmentioning

confidence: 99%

“…From sorted and aligned stacks, the quantification of injury volume, inflammation, and tissue damage impact is done. The methodology is described in [ 20 ]. Briefly, the volume of the injury was lately calculated by the integration of its polynomial fit equation, according to the formula: V =

in which A is the cross-sectional area and x represents the width of the interval [a,b].…”

Section: Methodsmentioning

confidence: 99%

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A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage

González-Manteiga

Navarro-González

Sebestyén

et al. 2022

IJMS

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Brain damage is the major cause of permanent disability and it is particularly relevant in the elderly. While most studies focused on the immediate phase of neuronal loss upon injury, much less is known about the process of axonal regeneration after damage. The development of new refined preclinical models to investigate neuronal regeneration and the recovery of brain tissue upon injury is a major unmet challenge. Here, we present a novel experimental paradigm in mice that entails the (i) tracing of cortico-callosal connections, (ii) a mechanical lesion of the motor cortex, (iii) the stereological and histological analysis of the damaged tissue, and (iv) the functional characterization of motor deficits. By combining conventional microscopy with semi-automated 3D reconstruction, this approach allows the analysis of fine subcellular structures, such as axonal terminals, with the tridimensional overview of the connectivity and tissue integrity around the lesioned area. Since this 3D reconstruction is performed in serial sections, multiple labeling can be performed by combining diverse histological markers. We provide an example of how this methodology can be used to study cellular interactions. Namely, we show the correlation between active microglial cells and the perineuronal nets that envelop parvalbumin interneurons. In conclusion, this novel experimental paradigm will contribute to a better understanding of the molecular and cellular interactions underpinning the process of cortical regeneration upon brain damage.

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Section: Resultsmentioning

confidence: 99%

in which A is the cross-sectional area and x represents the width of the interval [a,b].…”

Section: Methodsmentioning

confidence: 99%

A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage

González-Manteiga

Navarro-González

Sebestyén

et al. 2022

IJMS

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“…Additionally, using the MK-801 binding technique, it has been found that mutants exhibit 16% fewer functional NMDA receptors [ 191 ]. Nrg1 haploinsufficiency leads to a decreased number of presynaptic excitatory terminals on PV+ cortical neurons, resulting in altered inhibitory/excitatory homeostasis by reducing excitatory input to PV cells [ 192 ].…”

Section: Genetic Modelsmentioning

confidence: 99%

“…Moreover, Erbb4 null mutant mice display lower numbers of PV+ interneurons and compromised GABA release [ 194 ]. Previous studies have shown that ErbB4 deficits impair the correct wiring of cortical neurons, affecting excitatory synapses between pyramidal neurons and PV+ cells [ 192 , 195 ], suggesting that the NRG1 receptor plays a critical role in excitatory/inhibitory circuit homeostasis.…”

Section: Genetic Modelsmentioning

confidence: 99%

Advantages and Limitations of Animal Schizophrenia Models

Białoń

Wąsik

2022

IJMS

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Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

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“…The current knowledge about the function of NRG1 are mainly from the experiments with the puri ed peptides of NRG1-ECD or ICD. However, the functions of endogenous Nrg1 and the neuron populations expressing Nrg1 are relatively unexplored [23,24]. A prerequisite for addressing this issue is to understand the cellular expression pattern of Nrg1 and the axon projection of Nrg1-expressing neurons.…”

Section: Introductionmentioning

confidence: 99%

Genetic labeling reveals cellular expression pattern of neuregulin 1 in mouse forebrain

Ding¹,

Ding

Wang

et al. 2022

Preprint

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Neuregulin 1 (Nrg1) encodes a neurotrophic factor and is genetically associated with schizophrenia, bipolar disorder and major depression. NRG1 has been shown to play important roles in neurodevelopment and neurotransmission. However, the knowledge about the cellular expression pattern of Nrg1 in mouse forebrain remains controversial and inconclusive. Here we used CRISPR/Cas9 techniques to generate Nrg1Cre/+ knockin mice which express the Cre recombinase immediately before the stop codon of Nrg1 gene. By crossing the Nrg1Cre/+ mice with Ai14 reporter mice which express fluorescent protein tdTomato in a Cre-dependent manner, we generated Nrg1 reporter mice which express tdTomato in cells where Nrg1 gene is actively transcribed. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Nrg1 in mouse forebrain regions including the olfactory bulb, cerebral cortex, striatum and hippocampus. We further performed stereotaxic injection of adeno-associated virus (AAV) which express tdTomato in a Cre-dependent way into different forebrain regions of adult Nrg1Cre/+ mice, and thus explored the distribution and axon projection of Nrg1-positive cells. These results provide fundamental information needed for the study of Nrg1 function in mouse forebrain. Moreover, the Nrg1Cre/+ mice generated here may represent a useful tool to study the function of neuronal populations expressing Nrg1.

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Nrg1 haploinsufficiency alters inhibitory cortical circuits

Cited by 13 publications

References 70 publications

A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage

A Novel In Vivo Model for Multiplexed Analysis of Callosal Connections upon Cortical Damage

Advantages and Limitations of Animal Schizophrenia Models

Genetic labeling reveals cellular expression pattern of neuregulin 1 in mouse forebrain

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