Insulin-like growth factor 1 regulates excitatory synaptic transmission in pyramidal neurons from adult prefrontal cortex.

Insulin-like growth factor 1 (IGF1) influences synaptic function in addition to its role in brain development and aging. Although the expression levels of IGF1 and IGF1 receptor (IGF1R) peak during development and decline with age, the adult brain has abundant IGF1 or IGF1R expression. Studies reveal that IGF1 regulates the synaptic transmission in neurons from young animals. However, the action of IGF1 on neurons in the adult brain is still unclear. Here, we used prefrontal cortical (PFC) slices from adult mice (∼8 weeks old) to characterize the role of IGF1 on excitatory synaptic transmission in pyramidal neurons and the underlying molecular mechanisms. We first validated IGF1R expression in pyramidal neurons using translating ribosomal affinity purification assay. Then, using whole-cell patch-clamp recording, we found that IGF1 attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of IGF1R or conditional knockdown of IGF1R in PFC pyramidal neurons. In addition, we determined that IGF1-induced decrease of EPSC amplitude was due to postsynaptic effect (internalization of a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors [AMPAR]) rather than presynaptic glutamate release. Finally, we found that inhibition of metabotropic glutamate receptor subtype-1 (mGluR1) abolished IGF1-induced attenuation of evoked EPSC amplitude and decrease of AMPAR expression at synaptic membrane, suggesting mGluR1-mediated endocytosis of AMPAR was involved. Taken together, these data provide the first evidence that IGF1 regulates excitatory synaptic transmission in adult PFC via the interaction between IGF1R-dependent signaling pathway and mGluR1-mediated AMPAR endocytosis.

Allopregnanolone Effects on Transmission in the Brain Stem Solitary Tract Nucleus (NTS).

During pregnancy, the progesterone metabolite, allopregnanolone (ALLO), becomes elevated and has been associated with altered levels within the CNS and resulting changes in GABAA receptor function. Pregnant animals poorly compensate reflexes for a decrease in blood pressure during hemorrhage. Previous works suggested that ALLO decreases baroreflex responses by central actions, however, the underlying mechanisms are poorly understood. In this study, we tested ALLO actions on visceral afferent synaptic transmission at second-order neurons within medial portions of the nucleus tractus solitarius (NTS) using hindbrain slices from non-pregnant female rats. Solitary tract (ST) stimulation-evoked excitatory postsynaptic currents (ST-eEPSCs) in NTS neurons directly connected to vagal afferents within the ST. ST-eEPSCs were functionally identified as monosynaptic by the latency characteristics (low jitter = standard deviation of latency, ≤200 µs) to ST stimulation. Such second-order neurons all displayed spontaneous inhibitory postsynaptic currents (sIPSCs), and low micromolar concentrations of ALLO increased frequency and decay time. At submicromolar concentrations, ALLO induced a tonic, GABAergic inhibitory current and suppressed ST-eEPSCs' amplitude. While GABAA receptor antagonist, bicuculline, blocked all ALLO effects, gabazine only blocked sIPSC actions. In current-clamp mode, ALLO perfusion increased failure of ST stimulation to trigger action potentials in most neurons. Thus, our results indicate that ALLO acts to suppress visceral afferent ST synaptic transmission at first synapses by activating pharmacologically distinct GABAA subtypes at different concentration ranges. This ALLO-mediated attenuated visceral afferent signal integration in NTS may underlie reflex changes in blood pressure during gestation.