Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior
- Tata Institute of Fundamental Research, India
- Centre for Cellular and Molecular Biology, India
- Jawaharlal Nehru Centre for Advanced Scientific Research, India
Abstract
Early adversity is a risk factor for the development of adult psychopathology. Common across multiple rodent models of early adversity is increased signaling via forebrain Gq-coupled neurotransmitter receptors. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke persistent mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of forebrain excitatory neurons during postnatal life (P2-14), but not in juvenile or adult windows, increased anxiety-, despair-, and schizophrenia-like behavior in adulthood. This was accompanied by an enhanced metabolic rate of cortical and hippocampal glutamatergic and GABAergic neurons. Furthermore, we observed reduced activity and plasticity-associated marker expression, and perturbed excitatory/inhibitory currents in the hippocampus. These results indicate that Gq signaling mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as functional changes in forebrain glutamate and GABA systems, recapitulating aspects of the consequences of early adversity.
Data availability
All data generated or analysed during are included in the manuscript and supporting files. Source data files have been provided for Figure 2 and Figure 3.
Article and author information
Author details
Sthitapranjya Pati
Funding
Tata Institute of Fundamental Research (RTI4003)
- Vidita A Vaidya
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were carried out in strict accordance with the guideline of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India. Experiments and use of animals were approved by the institutional ethics committees of the Tata Institute of Fundamental Research, Mumbai, India (TIFR/IAEC/2017-2; 56/GO/ReBi/S/99/CPCSEA); Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India ( JPC001, JPC005; 201/GO/Re/S/2000/CPCSEA); and Centre for Cellular and Molecular Biology, Hyderabad, India (IAEC 32/2018; 20/GO/RBi/S/99/CPCSEA). Care was taken across all experiments to minimize animal suffering and restrict the number of animals used.
Copyright
© 2020, Pati et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior
eLife 9:e56171.
https://doi.org/10.7554/eLife.56171
Further reading
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We present near-atomic-resolution cryoEM structures of the mammalian voltage-gated potassium channel Kv1.2 in open, C-type inactivated, toxin-blocked and sodium-bound states at 3.2 Å, 2.5 Å, 3.2 Å, and 2.9 Å. These structures, all obtained at nominally zero membrane potential in detergent micelles, reveal distinct ion-occupancy patterns in the selectivity filter. The first two structures are very similar to those reported in the related Shaker channel and the much-studied Kv1.2–2.1 chimeric channel. On the other hand, two new structures show unexpected patterns of ion occupancy. First, the toxin α-Dendrotoxin, like Charybdotoxin, is seen to attach to the negatively-charged channel outer mouth, and a lysine residue penetrates into the selectivity filter, with the terminal amine coordinated by carbonyls, partially disrupting the outermost ion-binding site. In the remainder of the filter two densities of bound ions are observed, rather than three as observed with other toxin-blocked Kv channels. Second, a structure of Kv1.2 in Na+ solution does not show collapse or destabilization of the selectivity filter, but instead shows an intact selectivity filter with ion density in each binding site. We also attempted to image the C-type inactivated Kv1.2 W366F channel in Na+ solution, but the protein conformation was seen to be highly variable and only a low-resolution structure could be obtained. These findings present new insights into the stability of the selectivity filter and the mechanism of toxin block of this intensively studied, voltage-gated potassium channel.
