Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

Banerjee, Toshali; Pati, Sthitapranjya; Tiwari, Praachi; Vaidya, Vidita A.

doi:10.1101/2022.04.04.487022

2022

DOI: 10.1101/2022.04.04.487022

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Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

Toshali Banerjee

Sthitapranjya Pati

Praachi Tiwari

et al.

Abstract: Animal models of early adversity or neurodevelopmental disorders are associated with altered parvalbumin (PV)-positive inhibitory interneuron number and function, correlated with a dysregulated excitation-inhibition (E/I) balance that is implicated in the pathophysiology of neuropsychiatric disorders. We sought to address whether altering neuronal activity of PV-positive interneurons during the postnatal developmental window influences the emergence of anxio-depressive behaviors in adulthood, which are known t… Show more

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2023

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Cited by 2 publications

References 95 publications

(143 reference statements)

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Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors

Woodward

Rangel‐Barajas

Ringland

et al. 2023

eNeuro

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Women are twice as likely as men to experience emotional dysregulation after stress, resulting in substantially higher psychopathology for equivalent lifetime stress exposure, yet mechanisms underlying this vulnerability remain unknown. Studies suggest changes in medial prefrontal cortex (mPFC) activity as a potential contributor. Whether maladaptive changes in inhibitory interneurons participate in this process, and whether adaptations in response to stress differ between men and women, producing sex-specific changes in emotional behaviors and mPFC activity, remained undetermined. This study examined whether unpredictable chronic mild stress (UCMS) in mice differentially alters behavior and mPFC parvalbumin (PV) interneuron activity by sex, and whether these neurons’ activity drives sex-specific behavioral changes. Four weeks of UCMS increased anxiety- and depressive-like behaviors associated with FosB activation in mPFC PV neurons, particularly in females. After 8 weeks of UCMS, both sexes displayed these behavioral and neural changes. Chemogenetic activation of PV neurons in UCMS-exposed and non-stressed males induced significant changes in anxiety-like behaviors. Importantly, patch-clamp electrophysiology demonstrated altered excitability and basic neural properties on the same timeline as the emergence of behavioral effects: changes in females after 4 weeks and in males after 8 weeks of UCMS. These findings show, for the first time, that sex-specific changes in prefrontal PV neurons’ excitability parallel the emergence of anxiety-like behavior, revealing a potential novel mechanism underlying the enhanced vulnerability of females to stress-induced psychopathology, and supporting further investigation of this neuronal population to identify new therapeutic targets for stress disorders.Significance StatementWhile adult women are more often diagnosed with a mood disorder after facing stressful events than men, the mechanisms responsible for this sex-specific vulnerability remain unknown. This study uses a mouse model of stress-induced anxiety- and depressive-like behaviors to show a novel mechanism, adaptation of prefrontal parvalbumin neurons, that may underlie the greater susceptibility of females to stress-related psychopathologies. Female parvalbumin neurons adapt after shorter periods of chronic stress than male neurons, paralleling earlier emergence of anxiety-like behaviors in females. We propose that prefrontal PV interneurons are an important contributor to female stress sensitivity that should be further investigated to identify new therapies for psychopathology related to stress.

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Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors

Woodward

Rangel‐Barajas

Ringland

et al. 2023

eNeuro

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show abstract

Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments

et al. 2023

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Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a primary genetic cause of autism spectrum disorder (ASD). FXS arises from the silencing of the FMR1 gene causing the lack of translation of its encoded protein, the Fragile X Messenger RibonucleoProtein (FMRP), an RNA-binding protein involved in translational control and in RNA transport along dendrites. Although a large effort during the last 20 years has been made to investigate the cellular roles of FMRP, no effective and specific therapeutic intervention is available to treat FXS. Many studies revealed a role for FMRP in shaping sensory circuits during developmental critical periods to affect proper neurodevelopment. Dendritic spine stability, branching and density abnormalities are part of the developmental delay observed in various FXS brain areas. In particular, cortical neuronal networks in FXS are hyper-responsive and hyperexcitable, making these circuits highly synchronous. Overall, these data suggest that the excitatory/inhibitory (E/I) balance in FXS neuronal circuitry is altered. However, not much is known about how interneuron populations contribute to the unbalanced E/I ratio in FXS even if their abnormal functioning has an impact on the behavioral deficits of patients and animal models affected by neurodevelopmental disorders. We revise here the key literature concerning the role of interneurons in FXS not only with the purpose to better understand the pathophysiology of this disorder, but also to explore new possible therapeutic applications to treat FXS and other forms of ASD or ID. Indeed, for instance, the re-introduction of functional interneurons in the diseased brains has been proposed as a promising therapeutic approach for neurological and psychiatric disorders.

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Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

Cited by 2 publications

References 95 publications

Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors

Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors

Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments

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