Summary: Abnormal activation of parvalbumin neurons in the young mouse auditory cortex manifests as maternal neglect.
Source: Cold Spring Harbor Laboratory
The brain undergoes dramatic change during the first years of life. Its circuits readily rewire as an infant and then child encounters new sights and sounds, taking in the world and learning to understand it. As the child matures and key developmental periods pass, the brain becomes less malleable–but certain experiences create opportunities for parts of the adult brain to rewire and learn again.
Cold Spring Harbor Laboratory (CSHL) scientists have been studying one such period of transformation in mice: the time during which an adult female first learns to recognize and respond to the distress cries of young mouse pups. The research, reported January 7, 2020 in the Journal of Neuroscience, suggests that the same mechanisms that enable rapid learning during early development come into play when a period of heightened learning is triggered during adulthood. The findings hint at potential therapeutic strategies for a rare neurodevelopmental disorder called Rett syndrome, in which the adult brain may be unable to benefit from the rewiring opportunities.
A few years ago, CSHL Associate Professor Stephen Shea and colleagues discovered that female mice that lack two functional copies of a gene called Mecp2 failed to learn to retrieve distressed young. The scientists traced this parental neglect to the abnormal behavior of a group of neurons in the brain’s auditory cortex called parvalbumin (PV) neurons. PV neurons are inhibitory neurons: their signals dampen the activity of other brain cells. During development, the signals of PV neurons help close the critical periods during which the brain is most receptive to change.
The latest work from the Shea team, led by postdoctoral researchers Billy Lau and Keerthi Krishnan, and conducted in collaboration with CSHL Professor Josh Huang, took a closer look at how exposure to the young pups changes signaling within the auditory cortex of female mice. By monitoring the activity of individual cells in this part of the brain, the researchers found that when Mecp2 is intact, inhibitory signaling from PV neurons decrease following exposure to an encounter with pups. This inhibitory signaling allows other neurons in the circuit to become more responsive to the young animals’ cries. “The inhibitory networks sort of back off and allow the excitatory activity to be stronger,” Shea explains.
It’s not yet known exactly how pups trigger these changes in the female mice, but they occurred as long as MECP2 was present–even in mice that had never been pregnant. In female mice whose Mecp2 genes were impaired, however, the PV neurons’ signals remained strong.
In humans, mutations in Mecp2 cause Rett syndrome. Children with Rett syndrome appear develop normally for the first several months of life, but later begin to lose language and motor skills. The new findings from Shea’s team support previous evidence that PV neurons are particularly vulnerable to loss of MECP2. This suggests that these cells or the circuits they are involved in may be appropriate targets for drug development.
It also suggests that patients with Rett syndrome may be most responsive to treatment during certain developmental periods. Shea says prior to pup exposure, cells in the auditory cortex behaved the same in the brains of mice with impaired Mecp2 as they did in other mice. “That suggests that Mecp2 is specifically important during windows of heightened learning. That principle might guide treatments that are focused in time, at certain developmental milestones.”
About this neuroscience research article
Source: Cold Spring Harbor Laboratory Media Contacts: Sara Roncero-Menendez – Cold Spring Harbor Laboratory Image Source: The image is credited to Shea lab/CSHL, 2020.
Maternal experience-dependent cortical plasticity in mice is circuit- and stimulus-specific and requires MECP2
The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2. Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in wild-type adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally-relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het, suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically-relevant behavior.
Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups’ distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in non-mutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.