Prithviraj Rajebhosale
Oct 23, 2024; 44:e0063242024-e0063242024
Cellular

Holly Oakley
Oct 4, 2006; 26:10129-10140
Neurobiology of Disease

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by -secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V₃₂₁L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V₃₂₁L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V₃₂₁L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V₃₂₁L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V₃₂₁L mouse and humans with SCZ.

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system. Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic proregenerative molecular machinery in neurons, but the detailed mechanisms driving this effect are not fully understood. We evaluated how microRNAs are regulated in retinal neurons in response to intraocular inflammation to identify their potential role in axon regeneration. We found that miR-383-5p is downregulated in retinal ganglion cells in response to zymosan-induced intraocular inflammation. MiR-383-5p downregulation in neurons is sufficient to promote axon growth in vitro, and the intravitreal injection of a miR-383-5p inhibitor into the eye promotes axon regeneration following optic nerve crush. MiR-383-5p directly targets ciliary neurotrophic factor (CNTF) receptor components, and miR-383-5p inhibition sensitizes adult retinal neurons to the outgrowth-promoting effects of CNTF. Interestingly, we also demonstrate that CNTF treatment is sufficient to reduce miR-383-5p levels in neurons, constituting a positive-feedback module, whereby initial CNTF treatment reduces miR-383-5p levels, which then disinhibits CNTF receptor components to sensitize neurons to the ligand. Additionally, miR-383-5p inhibition derepresses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the proregenerative effects associated with miR-383-5p loss-of-function in vitro. We have thus identified a positive-feedback mechanism that facilitates neuronal CNTF sensitivity in neurons and a new molecular signaling module that promotes inflammation-induced axon regeneration.

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.

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