MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior
In the field of neuroscience, synaptic organization and plasticity are crucial for cognitive functions such as memory and social behavior. As rare synaptic inhibitory factors, members of the family known as MAM domain-containing glycosylphosphatidylinositol anchor proteins (MDGA) play an important regulatory role in synapse formation by inhibiting the formation of the neurexin-neuroligin complex of neural cell adhesion molecules, thus regulating synaptic organization. Although MDGA2 is expressed in various cell types and localized in excitatory and inhibitory synapses, the impact of MDGA2 loss of function on specific cell types and networks may differ depending on selective strategies for specific cell types and brain regions. Based on this, researchers generated conditional knockout mice of MDGA2 restricted to CA1 pyramidal cells (conditional knockout of MDGA2, abbreviated as MDGA2 CKO) to address this issue. The following is a comprehensive report on this study.
Synaptic organizing factors play a fundamental role in neural development, transmission, and plasticity.
MDGA proteins, which act as rare synaptic inhibitors, contribute to the synaptic organization process by inhibiting the neurexin-neuroligin complex that forms synapses. Previous analysis of single-copy MDGA2 deficient mice revealed upregulation of glutamatergic synapses and autism-like behaviors. However, considering the expression of MDGA2 in multiple cell types, researchers generated mice with MDGA2 knockout specifically restricted to CA1 pyramidal neurons.
This study reports that MDGA2 selectively inhibits the density and function of excitatory synapses on pyramidal neurons in the mature hippocampus. Conditional knockout of MDGA2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses, as no changes were detected in the properties of miniature and spontaneous inhibitory postsynaptic potentials. Functionally, evoked basal synaptic transmission and AMPA receptor currents were enhanced at glutamatergic inputs. At the behavioral level, memory in MDGA2 CKO mice appeared to be impaired, as both novel object recognition and contextual fear conditioning performance were compromised, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of autistic social deficits, was similarly impaired.
These results suggest that MDGA2 restricts the properties of excitatory synapses on CA1 neurons in mature hippocampal circuits, thereby optimizing the plasticity, cognition, and social behavior of this network.
Keywords include MDGA2, CA1 pyramidal neurons, glutamatergic input, synaptic plasticity, memory, social behavior, and autism.
This important academic article was jointly completed by a group of international experts and published in the July 2024 issue of Neuroscience Bulletin (Neurosci. Bull.) Volume 40, Issue 7, with the DOI 10.1007/s12264-023-01171-1. The research was jointly conducted by multiple research institutions, including the Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences. The co-first authors of the article are Wang Xuehui, Lin Donghui, and Jiang Jie, with corresponding authors Jiang Kewen, Connor Steven E, and Xie Yicheng. The motivation for this study was to further explore the role of MDGA2 in neural circuits at different developmental stages, especially its role in specific neuron types, and its regulatory function in learning, memory, and social behavior.
The research involved specifically knocking out MDGA2 in pyramidal neurons of the CA1 region in adult mice, using various experimental techniques including stereotactic surgery, virus injection, immunohistochemistry, quantitative reverse transcription PCR, in situ hybridization, and Western blotting. Data analysis involved action potentials, postsynaptic currents, homotypic action potentials, and behavioral experimental results.
The study found that knocking out MDGA2 in CA1 pyramidal neurons increased the density and function of excitatory synapses, while the properties of inhibitory synapses remained unchanged. This research not only elucidates the ongoing role of MDGA2 in mature hippocampal circuits but also suggests MDGA2 as a key molecule in autism spectrum disorders and a potential therapeutic target for regulating function, cognition, and social behavior.
This finding provides new insights into our understanding of the synaptic basis of neuropsychiatric disorders and may offer new directions for future therapeutic strategies.