Research ReportNeuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus
Introduction
Epilepsy is a common neurological disorder that affects ~ 1% of the population worldwide (Holden et al., 2005). In cases of chronic epilepsy with poorly controlled seizures, the frequency and/or severity of seizures often increases with time and patients can experience progressive cognitive decline (Aldenkamp and Bodde, 2005). The neurological basis by which seizures facilitate subsequent seizures and enhance cognitive decline is the subject of intense investigation. In animal models of epilepsy a number of critical processes have been identified including alterations in synaptic inhibition (Sloviter, 1987), changes in intrinsic excitability (Bernard et al., 2004), cell loss (Naegele, 2007), and axonal sprouting (Sutula et al., 1988).
In addition to these processes, epileptiform activity induces long term potentiation of excitatory synaptic transmission in the hippocampus. In animal models epileptiform activity induced by GABAA antagonists (Schneiderman, 1997, Abegg et al., 2004, Debanne et al., 2006), kainic acid (Ben-Ari and Gho, 1988), high potassium (Fleck et al., 1992, Morgan and Teyler, 2001) and electrical stimulation (Sutula and Steward, 1986, Stasheff et al., 1989) produce long term potentiation (LTP). Synaptic potentiation during epileptiform activity is critical for the subsequent development of spontaneous bursting. Thus, blockade of LTP during epileptiform activity prevents the induction of bursting (Debanne et al., 2006). Strengthening of excitatory synapses appears to be important for the development of seizures because it enhances interactions between excitatory neurons in the hippocampal network. This enhancement of excitatory drive shifts the balance of excitation and inhibition toward excitation, thereby favoring synchronized epileptiform activity (Bains et al., 1999, Staley et al., 2001). Burst-induced potentiation could therefore produce increases in the size of an epileptic focus or facilitate the spread of activity out of a focus. In addition, synaptic strengthening during seizures could interfere with memory mechanisms by occluding or blocking synaptic plasticity required for normal memory function (Schneiderman, 1997, Hsu et al., 2000, Debanne et al., 2006). Strategies aimed at preventing synaptic strengthening caused by seizures may therefore have clinical value.
In this study we have investigated the effect of the growth factor neuregulin on synaptic strengthening produced by epileptiform activity. Neuregulins are a family of growth factors important in early CNS development (Esper et al., 2006). In the adult brain the function of neuregulin is poorly understood although increasing evidence implicates neuregulin as one of the susceptibility genes for schizophrenia (Owen et al., 2005). Neuregulin-1 (NRG1) and its ErbB tyrosine kinase receptors (ErbB 1–4) are highly expressed in the adult brain, including hippocampal pyramidal neurons (Garcia et al., 2000, Huang et al., 2000, Law et al., 2004). Neuregulin accumulates at central synapses and is released in an activity dependent manner (Ozaki et al., 2004). Kainic acid induced seizures, forced locomotion and tetanic stimulation transiently upregulate neuregulin release and ErbB expression (Eilam et al., 1998, Loeb et al., 2002). In adult brain, ErbB and NMDA receptors colocalize at glutamatergic synapses and interact with PDZ-domain scaffolding proteins (Garcia et al., 2000, Huang et al., 2000). Neuregulin suppresses synaptic plasticity. At Schaffer collateral synapses on CA1 pyramidal neurons NRG1β prevents (Huang et al., 2000) or reverses LTP (Kwon et al., 2005). NRG1β has been reported to reverse LTP by promoting internalization of GluR1-containing AMPA receptors at potentiated synapses (Kwon et al., 2005). Based on these findings, we proposed that neuregulin might suppress synaptic strengthening produced by epileptiform activity. We demonstrate that a brief period of high K+-induced epileptiform activity produces synaptic potentiation and suppresses the subsequent induction of LTP. NRG1β blocks synaptic strengthening after epileptiform activity and allows subsequent stimulus trains to induce LTP. These findings indicate a role for neuregulin in limiting plasticity induced by epileptiform activity and suggest that neuregulin may reduce the generation and spread of seizures as well as memory deficits associated with epilepsy.
Section snippets
Neuregulin 1β blocks long term potentiation
To examine the effects of neuregulin on synaptic transmission and plasticity we tested the effect of the NRG1β peptide on fEPSPs recorded in the CA1 region of rat hippocampal slices. The NRG1β peptide contains the EGF domain sufficient for ErbB receptor activation; moreover the β isoform is prevalent in the CNS (Buonanno and Fischbach, 2001). NRG1β (10 nM) had no effect on baseline synaptic transmission (baseline in NRG1β 100 ± 0.2% of control, p = 0.3, n = 4; Fig. 1 A). We then delivered stimulus
Discussion
The principal finding of this study is that neuregulin reversed potentiation after epileptiform activity and preserved the dynamic range of synaptic plasticity at CA1 synapses. Neuregulin suppressed burst-induced potentiation without affecting baseline responses or suppressing fEPSPs below baseline levels. NRG1β did not alter neuronal excitability, NMDA fEPSPs or recurrent GABAergic inhibition, but acted only to reverse activity dependent changes.
The inability of NRG1β to affect paired pulse
Preparation of hippocampal slices
Transverse brain slices (500 μM thick) were prepared from isoflurane-anesthetized male Sprague–Dawley rats (35–42 days old) using a vibratome (Leica VT1000S, Nussloch, Germany). Brain slices were incubated in room temperature ACSF (artificial cerebrospinal fluid) containing (in mM): 125 NaCl, 2.7 KCl, 1.25 NaH2PO4, 25 NaHCO3, 10 glucose, 2 mM CaCl2, 1 mM MgCl2, bubbled with a 95% O2/5% CO2 gas mixture to pH 7.4. Osmolarity was 305 mOsm. Slices were allowed to incubate at least 1 h prior to
Acknowledgments
This work was supported by the South Carolina Research Foundation and the University of South Carolina Research Opportunity Program (DDM).
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