GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway.

Metabotropic glutamate receptor 2 (GRM2) is highly expressed in hippocampal dentate granule cells (DGCs), regulating synaptic transmission and hippocampal functions. Newborn DGCs are continuously generated throughout life and express GRM2 when they are mature. However, it remained unclear whether and how GRM2 regulates the development and integration of these newborn neurons. We discovered that the expression of GRM2 in adult-born DGCs increased with neuronal development in mice of both sexes. Lack of GRM2 caused developmental defects of DGCs and impaired hippocampus-dependent cognitive functions. Intriguingly, our data showed that knockdown of Grm2 resulted in decreased b/c-Raf kinases and paradoxically led to an excessive activation of MEK/ERK1/2 pathway. Inhibition of MEK ameliorated the developmental defects caused by Grm2 knockdown. Together, our results indicate that GRM2 is necessary for the development and functional integration of newborn DGCs in the adult hippocampus through regulating the phosphorylation and activation state of MEK/ERK1/2 pathway.SIGNIFICANCE STATEMENT Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature dentate granule cells (DGCs) in the hippocampus. It remains unclear whether GRM2 is required for the development and integration of adult-born DGCs. We provided in vivo and in vitro evidence to show that GRM2 regulates the development of adult-born DGCs and their integration into existing hippocampal circuits. Lack of GRM2 in a cohort of newborn DGCs impaired object-to-location memory in mice. Moreover, we revealed that GRM2 knockdown paradoxically upregulated MEK/ERK1/2 pathway by suppressing b/c-Raf in developing neurons, which is likely a common mechanism underlying the regulation of the development of neurons expressing GRM2. Thus, Raf/MEK/ERK1/2 pathway could be a potential target for brain diseases related to GRM2 abnormality.

A short period of early life oxytocin treatment rescues social behavior dysfunction via suppression of hippocampal hyperactivity in male mice.

Early sensory experiences interact with genes to shape precise neural circuits during development. This process is vital for proper brain function in adulthood. Neurological dysfunctions caused by environmental alterations and/or genetic mutation may share the same molecular or cellular mechanisms. Here, we show that early life bilateral whisker trimming (BWT) subsequently affects social discrimination in adult male mice. Enhanced activation of the hippocampal dorsal CA3 (dCA3) in BWT mice was observed during social preference tests. Optogenetic activation of dCA3 in naive mice impaired social discrimination, whereas chemogenetic silencing of dCA3 rescued social discrimination deficit in BWT mice. Hippocampal oxytocin (OXT) is reduced after whisker trimming. Neonatal intraventricular compensation of OXT relieved dCA3 over-activation and prevented social dysfunction. Neonatal knockdown of OXT receptor in dCA3 mimics the effects of BWT, and cannot be rescued by OXT treatment. Social behavior deficits in a fragile X syndrome mouse model (Fmr1 KO mice) could also be recovered by early life OXT treatment, through negating dCA3 over-activation. Here, a possible avenue to prevent social dysfunction is uncovered.

Homeostatic Regulation of Astrocytes by Visual Experience in the Developing Primary Visual Cortex.

During postnatal development, sensory experience shapes the organization and function of cortical circuits. Previous studies focusing on experience-dependent plasticity of neurons have revealed a variety of mechanisms underlying cortical circuit rewiring. Emerging evidence shows that astrocytes play important roles in shaping cortical circuits through extensive interactions with different types of neurons and other glia cells. However, it remains unclear how astrocytes respond to sensory experience during postnatal development. In the present study, we profiled the maturation of astrocytes in the primary visual cortex (V1) at different postnatal stages. We then investigated the anatomical and physiological changes of astrocytes in V1 induced by multiple types of visual experience within 4 postnatal weeks. Compared with monocular deprivation during the critical period, binocular deprivation showed stronger impact on reactive astrocytes in V1. Moreover, long-term binocular deprivation significantly reduced the density of reactive astrocytes in layer 2/3 of V1 while strengthening gap junction couplings between astrocytes at the same time. Therefore, our data demonstrated that cortical astrocytes could undergo homeostatic plasticity in response to long-term changes of sensory inputs. The plasticity of astrocytes may interact with the plasticity of neurons to cooperatively shape cortical circuit refinement during postnatal development.

Reduced excitatory activity in the developing mPFC mediates a PVH-to-PVL transition and impaired social cognition in autism spectrum disorders.

Understanding the neuropathogenesis of impaired social cognition in autism spectrum disorders (ASD) is challenging. Altered cortical parvalbumin-positive (PV+) interneurons have been consistently observed in ASD, but their roles and the underlying mechanisms remain poorly understood. In our study, we observed a downward-shifted spectrum of PV expression in the developing medial prefrontal cortex (mPFC) of ASD mouse models due to decreased activity of PV+ neurons. Surprisingly, chemogenetically suppressing PV+ neuron activity during postnatal development failed to induce ASD-like behaviors. In contrast, lowering excitatory activity in the developing mPFC not only dampened the activity state and PV expression of individual PV+ neurons, but also replicated ASD-like social deficits. Furthermore, enhancing excitation, but not PV+ interneuron-mediated inhibition, rescued social deficits in ASD mouse models. Collectively, our findings propose that reduced excitatory activity in the developing mPFC may serve as a shared local circuitry mechanism triggering alterations in PV+ interneurons and mediating impaired social functions in ASD.

Involvement of LIN28A in Wnt-dependent regulation of hippocampal neurogenesis in the aging brain.

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.