226
227
µ 228
Ω 229
230
0 ppb 2000ppb DG subthreshold (µa) 91 ± 59 86 ± 68 max stim. (µa) 755 ± 287 n=37 678 ± 300 max PS (mv) 8.7 ± 3.9 7.7 ± 4.3 n=61 CA1 subthreshold (µa) 36 ± 26 32 ± 13 max stim. (µa) 225 ± 123 n=11 183 ± 71 n=18 max PS (mv) 14.8 ± 4.1 14.7 ± 4.7 231
2 FA FA exposed; 2000ppb LTPEPSP 232
3 FA pepsp 4 FA LTP TBS EPSP 10 V 233
5 LTP 0 TBS TBS 10 pepsp pepsp 234
6 FA LTP t-testtbs 10 pepsp pepsp 235
7 080,4002000ppb FA LTP 8 FA LTP 236
9 LTP 237
10 EPSP 11 LTP 238
239
CHANGES IN AMOUNT OF ACTIVE KINASES (%) 200 175 150 125 100 7 5 50 25 0 CaM KIIα * Cx CA1 CA3 DG CaM KIIβ PKCα * Control Formaldehyde p42mapk ** Cx CA1 CA3 DG Cx CA1 CA3 DG Cx CA1 CA3 DG 12 1. 240
250 Control CHANGES IN AMOUNT OF PROTEINS (%) 225 200 175 150 125 100 75 50 25 ** Synapsin I * ** Folmaldehyde GluR1 0 Cortex CA1 CA3 DG Cortex CA1 CA3 DG 13 241
150 CHANGES IN CRH LEVELS (%) 125 100 75 50 25 * Control Folmaldehyde 0 Cortex Hippocampus 14 242
15 243
16 244
17 245
18 246
247
248
249
Abstract Electrophysiological, neurochemical and behavioral analysis on disturbance of neuronal information processing in mice chronically exposed to a low concentration of formaldehyde Yukiko FUETA 1, Kiyohisa NATSUME 2, Kohji FUKUNAGA 3, Shuji AOU 2 (The authors were in equal contribution.) 1 Department of Medical Technology I, School of Health Sciences, University of Occupational and Environmental Health 2 Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology 3 Department of Pharmacology, Tohoku University, Graduate School of Pharmacology Sciences To investigate effects of long-term inhalation (12w) of a low concentration of formaldehyde (FA) on neuronal information processing in the hippocampal formation, we analyzed paired-pulse responses of population spike (PS) and field excitatory postsynaptic potential (fepsp), and long-term potentiation (LTP) using slices, and then combined the 250
electrophysiological results with neurochemical study of intracellular signaling. LTP induced by a-burst stimulation applied to Schaffer collaterals in the CA1 was significantly suppressed in the mice exposed to 80, 400 and 2000 ppb FA. In mice exposed to 2000ppb FA, granule cell disinhibition in the dentate gyrus and a decrease in paired-pulse inhibition of fepsps in the CA1 were confirmed. The electrophysiological results suggest that inhibitory system and memory processing can be impaired in the mice exposed to FA. Since the suppression of LTP induction was observed following exposure to FA, we next investigated amount of the active forms of CA 2+ /calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) which are involved in the hippocampal LTP induction. We also assessed amount of the synaptic components such as synapsin I and an AMPA type glutamate receptor (GluR1 subunit). The amount of active CaMKII and CaMKII significantly increased in the CA1 without changes in the active PKC. Significant increases in amount of synapsin I in the CA1 region and the DG were also evident in the FA-exposed mice. An open field test disclosed an increase in searching behavior, rearing, while there was no change in the fear behavior of the FA-exposed mice in the elevated maze test. The abnormalities in the expression of the signaling molecules and synaptic components may be associated with the suppression of LTP induction and disturbance of the neural functions by exposure to FA. 251