Neurons in the brain must establish a balanced network of excitatory and inhibitory synapses during development for the brain to function properly. An imbalance between these synapses underlies various neurological and psychiatric disorders. The formation of excitatory and inhibitory synapses requires precise molecular control. In the hippocampus, the structure crucial for learning and memory, fibroblast growth factor 22 (FGF22) and FGF7 specifically promote excitatory or inhibitory synapse formation, respectively. Knockout of either Fgf gene leads to excitatory-inhibitory imbalance in the mouse hippocampus and manifests in an altered susceptibility to epileptic seizures, underscoring the importance of FGF-dependent synapse formation. However, the receptors and signaling mechanisms by which FGF22 and FGF7 induce excitatory and inhibitory synapse differentiation are unknown. Here, we show that distinct sets of overlapping FGF receptors (FGFRs), FGFR2b and FGFR1b, mediate excitatory or inhibitory presynaptic differentiation in response to FGF22 and FGF7. Excitatory presynaptic differentiation is impaired in Fgfr2b and Fgfr1b mutant mice; however, inhibitory presynaptic defects are only found in Fgfr2b mutants. FGFR2b and FGFR1b are required for an excitatory presynaptic response to FGF22, whereas only FGFR2b is required for an inhibitory presynaptic response to FGF7. We further find that FGFRs are required in the presynaptic neuron to respond to FGF22, and that FRS2 and PI3K, but not PLCγ, mediate FGF22-dependent presynaptic differentiation. Our results reveal the specific receptors and signaling pathways that mediate FGF-dependent presynaptic differentiation, and thereby provide a mechanistic understanding of precise excitatory and inhibitory synapse formation in the mammalian brain.

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The causal relationships between problematic internet use and psychological distress remain controversial. The present study investigated the reciprocal relationships between problematic internet use (PIU, i.e., problematic social media use [PSMU], problematic gaming [PG]) and psychological distress (i.e., anxiety, depression). Hong Kong and Taiwan university students (N=645; nmale=266; mean=20.95 years [SD=5.63]) were recruited for a survey study, with follow-ups at three, six, and nine months after baseline assessment. The Bergen Social Media Addiction Scale, Internet Gaming Disorder-Short Form, and the Hospital Anxiety and Depression Scale were used to assess studied variables. Cross-lagged models were constructed to understand the reciprocal relationships between PIU and psychological distress. The level of anxiety significantly impacted the level of PSMU but not in the opposite direction. The level of PSMU significantly impacted the level of depression but not in the opposite direction. In addition, levels of PG and both types of psychological distress had reciprocal impacts on each another. Because PIU can lead to psychological distress, prevention programs on digital health are needed. Moreover, because there is a reciprocity between PG and psychological distress, psychological interventions to break the reciprocal relationship for those with serious PG and psychological distress are warranted.

We found a higher rate of clinically diagnosed depression in our cohort compared to the general population. However, when using the validated PHQ-8 survey, the rate of depression more closely approximated the national incidence. Further, a significant proportion of patients were undiagnosed and/or misdiagnosed by current clinical assessments. Standardizing preoperative depression screening using validated patient-centered tools may prevent the consequences of untreated depression.