Astrocyte Morphogenesis and Synaptogenesis

 

Nature volume 551, pages 192–197 (09 November 2017)

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Jeff A. Stogsdill, et.al.

Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA

Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA

Duke Institute for Brain Sciences (DIBS), Durham, North Carolina 27710, USA

[paraphrase]

Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.

Astrocytes actively participate in synapse development and function by secreting instructive cues to neurons. Through their perisynaptic processes, astrocytes maintain ion homeostasis, clear neurotransmitters and contribute to neuromodulatory signalling to control circuit activity and behaviour. These complex functions of astrocytes are reflected in their elaborate structure, with numerous fine processes that interact closely with synapses. Importantly, loss of astrocyte complexity is a common pathological feature in neurological disorders.

Despite the vital functions of astrocytes in brain development and physiology, it is unclear how their complex morphology is established. Furthermore, we do not know whether disruptions in astrocyte morphogenesis lead to synaptic dysfunction. We investigated these questions in the developing mouse primary visual (V1) cortex during postnatal days 1–21 (P1–P21), when astrocyte morphogenesis occurs concomitantly with synaptic development. Using Aldh1L1–EGFP BAC-transgenic mice, in which all astrocytes express enhanced green fluorescent protein (EGFP), we found that astrocytic coverage of the V1 neuropil increased profoundly from P7 to P21, coinciding with high rates of synaptogenesis. This increase was concurrent with the appearance of fine astrocytic processes, and only became significant between P7 and P14, when eye opening occurs, suggesting that vision drives this growth. Indeed, mice reared in the dark showed profoundly stunted astrocyte coverage of V1 but not of the auditory cortex.

Our findings also challenge the assumption that neuroligins are functional only within neurons in the brain. This is particularly important because gene mutations in neuroligins, including NLGN2, are associated with a number of neurological disorders such as autism and schizophrenia. Neuroligin dysfunction in disease has been postulated to alter the fine balance between inhibition and excitation in the brain. Here we demonstrate that astrocytic NL2 controls the balance of excitatory and inhibitory synaptic connectivity, indicating that synaptic pathologies associated with neuroligin mutations could originate from astrocytic dysfunction. A recent study found that glial progenitor cells from schizophrenic patients express significantly lower levels of NL1, NL2, and NL3 compared to controls. When these human glial progenitors were injected into mice, they caused neuronal dysfunction, perturbed animal behaviour and yielded abnormal astrocytic morphologies. In conclusion, our findings reveal how imperative it is to understand the full extent of neuroligin functions in all cell types of the brain to completely comprehend the pathophysiology of these disorders.

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