Box 1_Figure 5.
A summary illustration of the perspective mechanisms associated with dysconnectivity and behavioral deficits – from abnormal synaptic function and plasticity to failures of self-monitoring. A, Timeline of synaptic- and circuit-specific alterations and behavioral changes during developmental dysconnectivity. B-G, In response to normal and abnormal stimulation, synapses mediating local and long-range connections between different cell types exhibit sequential alterations through different mechanisms during development. B & C, The immediate responses (within 24 hours) to risk factors (RFs) are associated with both translational and posttranslational modifications such as receptor trafficking (B) related to epigenetic regulation (e.g., epigenetic histone acetylation, methylation, phosphorylation via activator or repressor) (C) 88, 203, resulting in changes in excitatory synaptic strength/synaptic scaling of both AMPA- & NMDA-EPSCs 204, 205 in prefrontal neurons which consequently disrupts E/I balance in the local prefrontal circuit. D & E, Later on, especially during adolescent development, NMDAR subunit-dependent homeostatic plasticity in inhibitory neurons occurs in cell-type and input-specific manner through a sliding threshold mechanism 197, 198, such as differential LTP induction in SST vs. LTD PV cells, respectively. NMDAR hypofunction would weaken or disrupt both normal Hebbian plasticity between prefrontal interneurons and long-range afferents, meanwhile reshape the homeostatic plasticity in the mPFC and its connections with downstream targets. F, These homeostatic changes in plasticity (as described in D & E), in turn, induce threshold shift and/or disconnectivity, resulting in a reduced metaplasticity 222, 229. G, Consequently, an aberrant local circuit and dysfunctional connections are formed, a new set point with a narrower dynamic range for information is adopted, and abnormal behavioral changes follow under an aberrant connectivity condition 230, 231. IN: interneuron; PN: pyramidal neuron; PPF: paired-pulse facilitation; PPD: paired-pulse depression; RFs: regulatory factors; TFs: transcription factors.