Montarolo Francesca, Rominto Anita Maria, Berrino Luna, Bertolotto Antonio, Laezza Fernanda, Tempia Filippo, Hoxha Eriola
Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy.
Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, TO, Italy.
Transl Psychiatry. 2025 Apr 9;15(1):136. doi: 10.1038/s41398-025-03361-z.
Depression is a mental illness characterized by despair behavior, inability to feel pleasure, and social withdrawal. Causes are not yet clarified, but stress is a condition that induces depression. Neuronal alterations, comprising maladaptive neuronal plasticity and excitability, are present in both responses to stress and depression. Fibroblast growth factor 14 (Fgf14) controls neuronal excitability and proper action potential firing by stabilizing voltage-dependent sodium (Na) channels into the axon. Fgf14-Na channels complex is regulated by glycogen synthase kinase 3. Recently, Fgf14 has been genetically associated to depression. However, little is known about its role in controlling stress-induced depression. This study demonstrates that female Fgf14 mice are resilient to depression, as reported by reduced level of despair behavior, anhedonia, and increased sociability. Also, a reduction of anxious-like behavior was highlighted. Fgf14 mice showed increased expression of cannabinoid receptor without alterations of dopaminergic system in mPFC, suggesting a link between Fgf14 and endocannabinoid system in the control mechanisms underlying depression. Neuronal activity was assessed by analyzing cFOS expression during basal and following acute stress induced by tail suspension test (TST). The analysis revealed that neuronal activation in mPFC and VTA was correlated to immobility, where ratio of cFOS expression over immobility was significantly higher in Fgf14 mice. This suggests that higher neuronal activity might be involved in resilience to depression. In resilient Fgf14 mice, TST-induced acute stress caused activation only in pyramidal neurons. Our findings suggest that Fgf14 is involved in stress-coping mechanisms and could be targeted to improve resilience to depression.
抑郁症是一种精神疾病，其特征为绝望行为、无法感受愉悦以及社交退缩。病因尚未明确，但压力是诱发抑郁症的一个因素。神经元改变，包括适应不良的神经元可塑性和兴奋性，在对压力和抑郁症的反应中均存在。成纤维细胞生长因子14（Fgf14）通过将电压依赖性钠（Na）通道稳定到轴突中来控制神经元兴奋性和正常动作电位发放。Fgf14-Na通道复合物受糖原合酶激酶3调节。最近，Fgf14在基因上与抑郁症相关。然而，关于其在控制应激诱导的抑郁症中的作用知之甚少。本研究表明，雌性Fgf14小鼠对抑郁症具有抵抗力，表现为绝望行为水平降低、快感缺失以及社交能力增强。此外，还突出显示了焦虑样行为的减少。Fgf14小鼠在内侧前额叶皮质（mPFC）中大麻素受体的表达增加，而多巴胺能系统未发生改变，这表明Fgf14与内源性大麻素系统在抑郁症潜在控制机制中存在联系。通过分析在基础状态下以及尾部悬吊试验（TST）诱导的急性应激后cFOS的表达来评估神经元活性。分析显示，mPFC和腹侧被盖区（VTA）中的神经元激活与不动状态相关，其中Fgf14小鼠中cFOS表达与不动状态的比值显著更高。这表明更高的神经元活性可能与对抑郁症的抵抗力有关。在具有抵抗力的Fgf14小鼠中，TST诱导的急性应激仅导致锥体神经元激活。我们的研究结果表明，Fgf14参与应激应对机制，并且可以作为改善对抑郁症抵抗力的靶点。
