Abstract
Among the hallmarks of major depressive disorders (MDD) are molecular, functional, and morphological impairments in the hippocampus. Recent studies suggested a key role for hippocampal GABAergic interneurons both in depression and in the response to its treatments. These interneurons highly express the chromatin-remodeler SMARCA3 which mediates the response to chronic antidepressants in an unknown mechanism. Using cell-type-specific molecular and physiological approaches, we report that SMARCA3 mediates the glutamatergic signaling in interneurons by repressing the expression of the neuronal protein, Neurensin-2. This vesicular protein associates with endosomes and postsynaptic proteins and is highly and selectively expressed in subpopulations of GABAergic interneurons. Upregulation of Neurensin-2 in the hippocampus either by stress, viral overexpression, or by SMARCA3 deletion, results in depressive-like behaviors. In contrast, the deletion of Neurensin-2 confers resilience to stress and induces AMPA receptor localization to synapses. This pathway which bidirectionally affects emotional behavior could be involved in neuropsychiatric disorders, and suggests novel therapeutic approaches.
Highlights
The hippocampus is a key brain region in the neuronal circuit that regulates cognitive and emotional processing
Using the Translating Ribosome Affinity Purification (TRAP) method, we found that both CCK and PV interneurons are highly enriched in SMARCA3 (Fig. S1a)
To elucidate if SMARCA3 in CCKor PV-expressing interneurons is involved in emotional behavior, we generated mice with conditional deletion of its encoding gene, Hltf [13] in CCK cells or in PV cells, and subjected them and their WT littermates to behavioral tests
Summary
The hippocampus is a key brain region in the neuronal circuit that regulates cognitive and emotional processing. It is implicated in many neurological and neuropsychiatric disorders, including depression [1]. The hippocampus is highly subjected to plastic changes. Human and preclinical studies indicate that in the depressed brain, the granule cells in the hippocampal dentate gyrus (DG) undergo functional and morphological impairments. These include dendritic atrophy accompanied by volume reduction [2], spine loss [3], attenuated activity [4], and downregulation of α-amino-3-hydroxy-5-methyl-4-
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