Role of ionotropic glutamate receptors in long-term potentiation in rat hippocampal CA1 oriens-lacunosum moleculare interneurons

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This "anti-Hebbian" form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum moleculare, the oriens-lacunosum moleculare (O-LM) cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca(2+)-permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner and exhibit LTP dependent on Ca(2+)-permeable AMPA receptors

Neuregulin 1 Type I Overexpression Is Associated with Reduced NMDA Receptor-Mediated Synaptic Signaling in Hippocampal Interneurons Expressing PV or CCK

Hypofunction of N-methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 (NRG1), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK). Here, we investigated ErbB4 expression and synaptic transmission in interneuronal populations of the hippocampus of transgenic mice overexpressing NRG1 type I (NRG1tg-type-I mice). Immunohistochemical analyses confirmed that ErbB4 was coexpressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1tg-type-I mice. NMDAR-mediated currents in interneurons expressing PV (including PV+ basket cells) or CCK were reduced in NRG1tg-type-I mice compared to their littermate controls. We found no difference in AMPA receptor-mediated currents. Optogenetic activation (5 pulses at 20 Hz) of local glutamatergic fibers revealed a decreased NMDAR-mediated contribution to disynaptic GABAergic inhibition of pyramidal cells in the NRG1tg-type-I mice. GABAergic synaptic transmission from either PV+ or CCK+ interneurons, and glutamatergic transmission onto pyramidal cells, did not significantly differ between genotypes. The results indicate that synaptic NMDAR-mediated signaling in hippocampal interneurons is sensitive to chronically elevated NGR1 type I levels. This may contribute to the pathophysiological consequences of increased NRG1 expression in SZ

Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1tg-type I) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1tg-type I mice showed normal memory performance, but in older NRG1tg-type I mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1tg-type I mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1tg-type I mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform

Altered hippocampal fast oscillations and GABAergic circuits in neuregulin 1 over-expressing mice

Neuregulin 1 (NRG1) is a growth factor implicated in neurodevelopment and postnatal maintenance of synaptic circuits. Its gene has been associated with schizophrenia, and the expression of the type I isoform (NRG1tyI) is increased in patients’ brains. Earlier behavioural phenotyping of mice over-expressing NRG1tyI revealed impairment in hippocampus-dependent spatial working memory. This present work investigates the effects of increased NRG1tyI expression on hippocampal network functioning in these mice. Fast network oscillations, specifically at gamma frequencies, were studied in CA3 hippocampal slices in a carbachol model using cellular and extracellular microelectrode recording techniques. The peak frequency of field potential oscillations was significantly reduced in slices from NRG1tyI mice compared to wild-type littermates. In addition, NRG1tyI mouse slices were more prone to develop epileptiform activity. During rhythmic activity, the balance of phasic excitation and inhibition was significantly altered in principal cells of NRG1tyI mice. Inhibitory synaptic input was more sustained, while excitatory synaptic currents were kinetically unchanged but larger and more variable in amplitude. Together, these data suggest altered functioning of the GABAergic inhibitory circuits that generate and maintain gamma oscillations. Because parvalbumin-expressing (PV+) interneurons are a major target of NRG1 signalling, the inhibition from PV+ interneurons to pyramidal cells was examined next. Channelrhodopsin-2-mediated photostimulation of PV+ cell axons failed to show changes in GABAergic inhibition of CA3 pyramidal cells in NRG1tyI mice. However, synaptic miniature glutamatergic neurotransmission was reduced in identified PV+ basket cells (BCs) and axo-axonic cells (AACs) but not in pyramidal cells. The change was expressed postsynaptically, affecting NMDA receptor- but not AMPA receptor-mediated currents. The data suggest that NRG1tyI over-expression results in alterations in PV+ interneuron types, particularly at the glutamatergic synapses that excite these cells. These changes and the altered gamma oscillations are already evident in late adolescence — before the age at which cognitive deficits are detectable.</p

Altered hippocampal fast oscillations and GABAergic circuits in neuregulin 1 over-expressing mice

Neuregulin 1 (NRG1) is a growth factor implicated in neurodevelopment and postnatal maintenance of synaptic circuits. Its gene has been associated with schizophrenia, and the expression of the type I isoform (NRG1tyI) is increased in patients’ brains. Earlier behavioural phenotyping of mice over-expressing NRG1tyI revealed impairment in hippocampus-dependent spatial working memory. This present work investigates the effects of increased NRG1tyI expression on hippocampal network functioning in these mice. Fast network oscillations, specifically at gamma frequencies, were studied in CA3 hippocampal slices in a carbachol model using cellular and extracellular microelectrode recording techniques. The peak frequency of field potential oscillations was significantly reduced in slices from NRG1tyI mice compared to wild-type littermates. In addition, NRG1tyI mouse slices were more prone to develop epileptiform activity. During rhythmic activity, the balance of phasic excitation and inhibition was significantly altered in principal cells of NRG1tyI mice. Inhibitory synaptic input was more sustained, while excitatory synaptic currents were kinetically unchanged but larger and more variable in amplitude. Together, these data suggest altered functioning of the GABAergic inhibitory circuits that generate and maintain gamma oscillations. Because parvalbumin-expressing (PV+) interneurons are a major target of NRG1 signalling, the inhibition from PV+ interneurons to pyramidal cells was examined next. Channelrhodopsin-2-mediated photostimulation of PV+ cell axons failed to show changes in GABAergic inhibition of CA3 pyramidal cells in NRG1tyI mice. However, synaptic miniature glutamatergic neurotransmission was reduced in identified PV+ basket cells (BCs) and axo-axonic cells (AACs) but not in pyramidal cells. The change was expressed postsynaptically, affecting NMDA receptor- but not AMPA receptor-mediated currents. The data suggest that NRG1tyI over-expression results in alterations in PV+ interneuron types, particularly at the glutamatergic synapses that excite these cells. These changes and the altered gamma oscillations are already evident in late adolescence — before the age at which cognitive deficits are detectable.This thesis is not currently available in ORA

Selection and socialization effects of studying abroad

Objectives Studying abroad is often considered a life-changing experience. However, research on studying abroad has not always disentangled selection from socialization effects, leading to uncertainty about the actual impact of this experience. In this 4-wave longitudinal study, we examined both selection and socialization effects of a 4-week intensive study abroad program on 17 psychosocial variables related to motivation, academic achievement, well-being, and self-reflection. Method We used propensity score matching and multiple-group growth curve models to examine selection and socialization effects in a sample of sojourners (n = 145) and non-sojourners (n = 291). Results We found selection effects for several variables related to students’ motivation and well-being. Contrary to our predictions, we found no evidence for socialization effects of studying abroad on any of the outcome variables. Conclusions Students who are relatively more intrinsically motivated and emotionally healthy appear to be more likely to study abroad. However, studying abroad for one month does not appear to lead to meaningful and lasting psychological change, on average. Our results highlight the need to examine both selection and socialization effects of study abroad programs with longitudinal data and well-matched comparison groups