the mouse hippocampus normal levels of kynurenic acid (KYNA) a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of l-kynurenine maintain a degree of tonic inhibition of α7 nicotinic acetylcholine receptors (nAChRs). (10 min) of the slices from postweaned rats with kynurenine (200 μM) had no significant effect on the magnitude of α7 nAChR responses. The peak amplitudes PIK3C1 of type IA currents recorded at 10 min after the beginning of superfusion with kynurenine-containing or kynurenine-free ACSF were 89.9 ± 3.9% (= 6 neurons) and 95.5 ± 1.4% (= 9 neurons) of the current amplitudes recorded before the start of superfusion; the difference between the two groups was not significant (= 0.134 by unpaired Student’s test). Therefore α7 nAChR inhibition in slices from postweaned rats could have resulted from kynurenine-derived KYNA. Although KYNA levels in the ACSF surrounding slices from postweaned rats increased significantly between 2 and SKLB610 6 h of incubation with kynurenine the magnitude of reduction of α7 nAChR responses did not change significantly during the same time (Fig. 2C). This finding suggests that the concentration of KYNA at its release sites remained constant but continuous diffusion into the surrounding ACSF resulted in a linear buildup of KYNA levels in the ACSF. Age-Dependent Effects of Incubation with Kynurenine on GABAergic PSCs Evoked by α7 nAChR Activation in Rat Hippocampal Slices. In the absence of bicuculline bursts of outward postsynaptic currents were recorded in response to U-tube application of choline (10 mM 12 pulse) from CA1 SRIs voltage clamped at 0 mV in control and kynurenine-exposed slices (Fig. 3A). The GABAergic nature of these currents was confirmed by their blockade with bicuculline (10 μM). EPSCs were absent at 0 mV the reversal potential for cationic currents. Fig. 3. Effects of kynurenine on α7 nAChR-dependent GABAergic PSCs in rat hippocampal slices. A sample recordings of outward-going GABAergic PSCs obtained from SRIs during U-tube application of choline (10 mM) to slices from preweaned (P10) and postweaned … As in previous studies (Alkondon et al. 1999 choline-evoked GABAergic PSCs were sensitive to blockade by 10 μM bicuculline and the α7 nAChR antagonists MLA (10 nM) and α-BGT (100 nM) and could not be detected in the presence of the Na+ channel blocker tetrodotoxin (100 nM). These results are consistent with the concept that choline-evoked GABAergic PSCs recorded from CA1 SRIs result from the activation of α7 nAChRs in interneurons that synapse onto the SKLB610 SRIs studied here. When hippocampal slices from preweaned (P10) or postweaned (P30) rats were exposed to kynurenine (200 μM) there was no significant change in the frequency amplitude 10 to 90% rise time or decay-time constant of spontaneous GABAergic PSCs recorded from CA1 SRIs SKLB610 (Table 1). Incubation of slices from P10 rats with kynurenine (200 μM) also had no significant effect on the net charge of choline-evoked GABAergic PSCs (Fig. 3B). However incubation of slices from P30 rats with kynurenine significantly decreased the net charge of choline-induced GABAergic PSCs (Fig. 3B). These results are consistent with the age-dependent inhibition of α7 nAChRs by kynurenine-derived KYNA described above. TABLE SKLB610 1 Characteristics of spontaneous GABAergic PSCs recorded in the presence and absence of kynurenine (200 μM) from CA1 SRIs in hippocampal slices from preweaned (P10) and postweaned SKLB610 (P30) rats Effects of Kynurenine on α7 nAChRs in Human Cerebral Cortical Neurons. As described under = 5 neurons in each group from three rats; = 0.45 according to one-way ANOVA). These results demonstrate that SKLB610 α7 nAChRs in immature hippocampal neurons are insensitive to inhibition by KYNA. Differential Effects of Endogenously..