The pharmacological specificity of glutamatergic receptors (iglur) on cortical network rhythms

Background It is clear that neuronal generated ensemble patterns in cortical structures are the source of cognitive behaviours and that disruption of temporal organization may underlie the various deficits observed in psychiatric disease. Cortical network level temporal correlations are often expressed in the form of oscillations. Such activity is preserved from murine and rodent brains to primate and human CNS. Moreover, this activity has been observed to be altered in animal models of psychiatric disease (1,2) and in untreated humans suffering from psychiatric diseases (3). It is therefore reasonable to assume that the potential to examine the actions of potential nootropic compounds using such patterns of activity offers unprecedented opportunities. It is clear from studies conducted in transgenic models that NMDA and AMPA receptors are critically important for neuronal populations at both the in vitro and behavioural level (4,5). Pre-clinical evidence indicates that glutamate receptor modulators can increase learning and memory capabilities at both the in vitro brain slices level and in the in vivo behaving condition. Modulators of both the NMDA and AMPA could potentially be a novel treatment for cognitive dysfunctions in psychiatric disease. However, there is a paucity of meaningful pre-clinical data with regard to this issue. Purposes i) To test in rat brain slices the hypothesis that positive AMPA modulators (PAMs) and glycine transporter 1 inhibitors (GU1I) can increase gamma frequency oscillations ii) To test in rat brain slices that can reverse disruptions of gamma frequency oscillations in animals models of psychosis ii) To identify the specific cellular and synaptic components on which PAMs and a GU1I act to bring about these changes Aim and objectives Objective 1: To examine the action of PAMs and a GU1I on rodent cortical gamma oscillations in vitro Extracellular field potential recordings will be obtained from rat brain slices in the neocortex, entorhinal cortex and hippocampus. Using established pharmacological protocols to induce gamma frequency oscillations (6,7,8), the actions of PAMSs (for e.g. Org 250455-0), a positive competitive control, and a GU1I will be examined. Extensive intracellular and multisite extracellular recordings will be performed from normal adult rats from cortical regions identified in objective 1. The main aim will be to follow up and examine in more detail key aspects of the modulation of gamma frequency oscillations induced by PAMs and a GU1I and to exploit the in vitro environment to concentrate on this modulation by examining the following: i) the effects of PAMs and a GU1I on macroscopic amplitude and frequency ii) the coherence of gamma oscillations across cortical and hippocampal sites in the presence and absence of the agents Objective 2: Using both acute and transgenic models available to the laboratory, the manipulation of both pharmacological targets will be tested to examine if restoration of disrupted network activity can be achieved. Objective 3: To identify the cellular and synaptic components which are responsible for the changes to gamma frequency oscillations by PAMs In combination with anatomical techniques, intracellular recordings from pyramidal cell and interneurons will focus on the action potential output and synaptic (glutamatergic) inputs onto these cells during gamma frequency oscillations and the impact that PAMs and a GU1I have on these factors References 1.Cunningham et al., (2006) J Neurosci. 26:2767-76 2.Driver et al., (2007) Eur J Neurosci. 26:1280-8 3.Spencer et al., (2003) J Neurosci. 23:7407-11 4.Fuchs et al., (2007) Neuron. 53:591-604 5.Middleton et al., (2008) Proc Natl Acad Sci U S A. 105:18572-7 6.Cunningham MO et al., (2003) J Neurosci. 23:9761-9 7.Cunningham MO et al., (2004) Proc Natl Acad Sci U S A. 101:7152-7 8.Fisahn et al., (1998) Nature 394:186-9.