Reduced inhibition of hippocampal neurons impairs long-term memory
recall in Rett syndrome

Date:
March 15, 2022
Source:
Baylor College of Medicine
Summary:
Researchers have discovered that diminished memory recall in Rett
syndrome mice can be restored by activating specific inhibitory
cells in the hippocampus.



FULL STORY ==========================================================================
An exciting study by researchers in the laboratory of Dr. Huda Zoghbi, distinguished service professor at Baylor College of Medicine and director
of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI)
at Texas Children's Hospital, has discovered that diminished memory
recall in Rett syndrome mice can be restored by activating specific
inhibitory cells in the hippocampus. The findings are published in the
current edition of Neuron.


==========================================================================
Rett syndrome is a neurodevelopmental disorder characterized by loss of acquired cognitive, motor, language and social skills after the first
year of life as well as profound learning and memory impairments. In particular, contextual memories, those that encode an event and the circumstances in which the event was experienced, are diminished in
mouse models of Rett syndrome.

Previous research has suggested that diminished contextual memories
result from disruptions in the finely tuned balance between excitatory and inhibitory synaptic inputs that constantly bombard hippocampal neurons.

Zoghbi's team hypothesized that disruptions in this balance may alter
the size and composition of ensembles of hippocampal neurons needed to
encode a contextual memory. Using a miniature microscope, they directly monitored these ensembles as mice recalled a fearful experience. They
found that Rett mice have larger and more correlated ensembles of neurons
than wild-type mice, suggesting that hippocampal pyramidal neurons are
not receiving enough inhibition in Rett mice. "An optimal balance between excitatory and inhibitory input is critical for the proper formation
and retrieval of contextual memories," said Lingjie He, postdoctoral
associate in the Zoghbi lab and first author.

The next big question that the team addressed was, Which neuron is not providing the inhibition? To hunt for this neuron, the team recorded
neuronal activity from identified cell types in brain slices. They
found a significant reduction in connectivity between pyramidal cells
and a subset of somatostatin-expressing (SOM) inhibitory neurons, the
OLM cells. They found that these cells, which are normally recruited
by hippocampal pyramidal neurons in healthy mice during memory recall,
were poorly engaged in Rett mice.

This led the team to wonder if activating these inhibitory neurons
during memory recall would help Rett mice remember better. To address
this, they selectively enhanced the activity of somatostatin cells in
the hippocampus using a chemical-genetic approach that allows for the activation of a specific cell type. Incredibly, activating somatostatin expressing cells in Rett mice restored contextual memory recall.

"This is the first study to demonstrate that upregulating the activity
of SOM neurons can improve memory recall and retrieval capacity in Rett
mice," said Zoghbi, Howard Hughes Medical Institute investigator. "It
opens exciting areas of research to explore therapeutic possibilities that could improve contextual memory recall in individuals affected by Rett syndrome. These findings have a much broader implication and are also applicable to other neurological disorders in which the development and function of inhibitory circuits are altered." Other authors involved
in the study are Matthew Caudill, Junzhan Jing, Wei Wang, Yaling Sun,
Jianrong Tang and Xiaolong Jiang. The authors are affiliated with one
or more of the following institutions: Jan and Dan Duncan Neurological
Research Institute, Baylor College of Medicine and Howard Hughes Medical Institute. The study was funded by Howard Hughes Medical Institute,
National Institutes of Health, Baylor College of Medicine, the Charif
Souki Fund and the Yasmine Gibellini fund.


========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Lingjie He, Matthew S. Caudill, Junzhan Jing, Wei Wang, Yaling Sun,
Jianrong Tang, Xiaolong Jiang, Huda Y. Zoghbi. A weakened
recurrent circuit in the hippocampus of Rett syndrome mice
disrupts long-term memory representations. Neuron, 2022; DOI:
10.1016/j.neuron.2022.02.014 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220315113005.htm

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