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Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a
Destynie Medeiros1, Likhitha Polepalli1, Wei Li1
1Department of Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca2+-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca2+ signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca2+ signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca2+ signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.
Insights
Mice lacking Mecp2 show social memory deficits due to altered brain activity. Specifically, medial prefrontal cortex neurons exhibit impaired excitation and heightened inhibition during social interactions.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Genetics
Background:
- Social memory deficits are observed in Mecp2 knockout (KO) mice, a model for Rett syndrome.
- These impairments are linked to altered neuronal activity in the ventral hippocampus (vHIP) to medial prefrontal cortex (mPFC) projection.
- The precise cellular mechanisms driving these social memory deficits in Mecp2 KO mice remain unclear.
Purpose of the Study:
- To investigate the cellular mechanisms underlying social memory impairments in Mecp2 KO mice.
- To examine neuronal activity in the vHIP-mPFC projection during social interactions.
- To differentiate between social memory and sociability deficits in Mecp2 KO mice.
Main Methods:
- Utilized a novel 4-chamber social memory arena combined with in vivo fiber photometry.
- Measured Ca2+ signals in mPFC pyramidal neurons (PYRs) and parvalbumin interneurons (PV-INs) during social interactions.
- Compared neuronal activity between Mecp2 KO mice and wildtype (WT) littermates.
Main Results:
- Mecp2 KO mice exhibited social memory deficits but not sociability issues.
- mPFC PYRs in WT mice showed increased Ca2+ signals during social interactions, while Mecp2 KO mice showed reduced signals.
- mPFC PV-INs in Mecp2 KO mice displayed larger Ca2+ signals during familiar social interactions compared to PYRs, unlike in WT mice.
Conclusions:
- Mecp2 deficiency leads to impaired excitation and heightened inhibition in the mPFC network during social interactions.
- These network alterations in the mPFC likely contribute to the observed social memory deficits in Mecp2 KO mice.
- Findings highlight the critical role of Mecp2 in regulating mPFC neuronal function essential for social memory.
