ErbB4 is a suppressor of long-term potentiation in the adult hippocampus - PubMed (original) (raw)

ErbB4 is a suppressor of long-term potentiation in the adult hippocampus

Graham M Pitcher et al. Neuroreport. 2008.

Abstract

ErbB4 has emerged as a leading susceptibility gene for schizophrenia but the function of the ErbB4 receptor in the adult brain is unknown. Here, we show in the adult hippocampus that long-term potentiation (LTP) of transmission at Schaffer collateral CA1 synapses was markedly enhanced in mutant mice lacking ErbB4. Concordantly, LTP was enhanced by acutely blocking ErbB4 in wild-type animals, indicating that ErbB4 activity constitutively suppresses LTP. Moreover, increasing ErbB4 signaling further suppressed LTP. By contrast, altering ErbB4 activity did not affect basal synaptic transmission or short-term facilitation. Our findings suggest that cognitive deficits in schizophrenia may be a consequence of hyperfunction of ErbB4 signaling leading to suppressed glutamatergic synaptic plasticity, thus opening new approaches for the treatment of this disorder.

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Conflict of interest statement

Disclaimer: The authors have no conflicts of interest to declare.

Figures

Fig. 1

Hippocampal ErbB4 expression and morphology in _ErbB4+/+_HER4heart and ErbB4−/−HER4heart mice. (a) ErbB4 immunoreactivity (shown in red) in a parasagittal hippocampal section from an adult _ErbB4+/+_HER4heart mouse. Scale bar, 200 μm. Right: Higher magnification fluorescent micrograph representing CA1 region indicated by the dotted line. Scale bar, 150 μm. (b) Adjacent _ErbB4+/+_HER4heart hippocampal coronal sections incubated with anti-ErbB4 antibody (left) or with anti-ErbB4 antibody pre-incubated with its antigenic peptide (right). ErbB4 immunoreactivity in red and NeuN immunoreactivity is shown in green. Scale bar, 100 μm. (c) Photomicrograph of hippocampal CA1 from an adult _ErbB4+/+_HER4heart mouse showing distribution of immunoreactivity for ErbB4 (red), MAP2 (blue) and NeuN (green). Scale bar, 25 μm (d) Western blot analysis of ErbB4 protein expression in _ErbB4+/+_HER4heart (+/+) and _ErbB4−/−_HER4heart (−/−) mice. (e) Nissl staining in parasagittal hippocampal sections from _ErbB4+/+_HER4heart (+/+) and _ErbB4−/−_HER4heart (−/−) mice. Scale bar, 200 μm.

Fig. 2

Loss of function of ErbB4 enhances tbLTP in CA1 hippocampus. (a) fEPSP slope and (b) fiber volley amplitude plotted as a function of stimulus intensity (_ErbB4+/+_HER4heart (ErbB4+/+), open circles; _ErbB4−/−_HER4heart (ErbB4−/−), filled circles). Strength of Schaffer collateral stimulation is indicated on the horizontal axis. Representative traces show fiber volley (open arrow) and fEPSPs (filled arrow; scale bars: 2 ms, 1 mV). In all panels, data are shown as mean ± SEM. (c) Paired-pulse facilitation of fEPSPs in slices from _ErbB4+/+_HER4heart (open circles) and _ErbB4−/−_HER4heart(filled circles) mice. Interstimulus interval is indicated on the horizontal axis. P1, first response; P2, second response. (d) Summary scatter plot shows grouped normalized fEPSP slope every 1 min in slices from _ErbB4+/+_HER4heart (open circles, n = 14 slices) and from _ErbB4−/−_HER4heart (filled circles, n = 14 slices) mice. Theta-burst stimulation was delivered to Schaffer collateral-CA1 synapses at the 30 min time point. fEPSP slope was normalized with respect to the mean slope of fEPSPs recorded during the 10 min period immediately before TBS. Inset: average of six consecutive fEPSPs recorded before or after TBS (‘a’ or ‘b’, respectively; scale bars: 10 ms, 0.5 mV). p < 0.01, _ErbB4+/+_HER4heart vs. _ErbB4−/−_HER4heart, 60 min after TBS.

Fig 3

Pharmacological inhibition of ErbB4 increases tbLTP in CA1 hippocampus and prevents the suppression of tbLTP by NRG-1β. (a) fEPSP slope and (b) fiber volley amplitude plotted as a function of stimulus intensity at rat Schaffer collateral-CA1 synapses in control slices (open circles) and in slices treated with NRG-1β (2 nM; black circles) or PD158780 (10 μM; gray circles). Strength of Schaffer collateral stimulation is indicated on the horizontal axis. In this and the subsequent panel, data are shown as mean ± SEM. (c) Paired-pulse facilitation of fEPSPs in control slices and in slices treated with NRG-1β (black circles) or PD158780 (gray circles). Interstimulus interval is indicated on the horizontal axis. P1, first response; P2, second response. (d) Summary scatter plot shows grouped normalized fEPSP slope plotted every 1 min in control (open circles, n = 13) and PD158780-treated (filled circles, n = 21; in ACSF beginning 25 min before TBS with final concentration of 10 μM) slices from rats. Inset: average of six consecutive fEPSPs recorded before or after TBS (‘a’ or ‘b’, respectively; scale bars: 10 ms, 0.6 mV). p < 0.001, control vs. PD158780, 60 min after TBS. (e) Histogram shows TBS-induced increase in fEPSP slope 60 min after TBS in slices from _ErbB4+/+_HER4heart (white bar) and _ErbB4−/−_HER4heart (dark gray bar) mice without (−) and with (+; black bars) NRG-1β treatment (in ACSF beginning 20 min before TBS with final concentration of 2 nM). Results are expressed as a percentage of TBS-induced increase in fEPSP slope (% tbLTP) with tbLTP in _ErbB4+/+_HER4heart slices (white bar) normalized to 100 %. *** p < 0.001 vs. _ErbB4+/+_HER4heart (white bar); p < 0.05, _ErbB4−/−_HER4heart/NRG-1β (black bar) vs. _ErbB4+/+_HER4heart (white bar). (f) Histogram shows normalized TBS-induced mean increase in fEPSP slope in control (white bar) and PD158780-treated slices (light gray bar) without (−) and with (+; black bars) NRG-1β (2 nM administered as above). *** p < 0.001 vs. control (white bar); p < 0.01, PD158780/NRG-1β (black bar) vs. control (white bar). Data are taken 60 min after TBS.

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ErbB4 is a suppressor of long-term potentiation in the adult hippocampus - PubMed (original) (raw)