PROJECT ABSTRACTSProject 1 - Molecular abnormalities in schizophrenia in distinct subsets of cortical GABA neurons thought to generate oscillatory activity
The central hypothesis of this Center posits that a distinctive pattern of molecular alterations in subsets of GABA neurons gives rise to disturbances in cortical network oscillations that underlie the information processing deficits of schizophrenia. Disturbances in markers of cortical GABA neurotransmission are common in schizophrenia and are most prominent in two types of GABA neurons: parvalbumin-positive (PV), fast-spiking neurons and somatostatin-positive (SST), low-threshold spiking neurons. PV and SST cells each form networks with neurons of the same type that are thought to play central roles in the generation of gamma (30-80 Hz) and theta (4-7 Hz) oscillations, respectively, both of which are disturbed in subjects with schizophrenia. Network oscillations depend, at least in part, on 3 physiological properties: 1) the strength [i.e., inhibitory post-synaptic current (IPSC) amplitude] of GABA neurotransmission as determined by both pre- and post-synaptic factors; 2) the kinetics (i.e., IPSC duration) of GABA neurotransmission as determined principally by the subunit composition of post-synaptic GABA-A receptors; and 3) the nature of the resulting inhibition (i.e., shunting or hyperpolarizing) as determined by chloride ion flow when GABA-A receptors are activated. Each of these physiological features is, in turn, dependent upon the expression of particular sets of gene products. Consequently, we hypothesize that the alterations in gamma and theta oscillations in schizophrenia reflect cell type-specific disturbances in the gene products that influence the strength, kinetics or nature of GABA-mediated inhibition. Studies in postmortem human brain, using the dorsolateral prefrontal cortex (DLPFC) as a prototypic cortical region affected in schizophrenia, will be conducted to determine if 1) the presynaptic strength of GABA neurotransmission in schizophrenia is impaired due to deficits in the amount of GAD67 protein available to synthesize GABA in PV and SST neurons; 2) if cell type-specific alterations in the expression of α1 and α2 GABA-A receptor subunits disrupt the kinetics of GABA neurotransmission in schizophrenia; and 3) if shifts in the expression of chloride transporters in schizophrenia disrupt the shunting inhibitory input to GABA neurons and/or the hyperpolarizing inhibitory input to pyramidal cells required for robust oscillations. The proposed studies are both methodologically and conceptually innovative, and these investigations depend upon and inform the studies proposed in other projects in this Center. Thus, the outcomes of the proposed studies are likely to be highly informative regarding both the disease mechanisms underlying oscillatory and information processing deficits in schizophrenia and in identifying novel molecular targets for treating these deficits.
Project 2 - Integrated computational, electrophysiological and anatomical approaches to determine the relationship between cell type-specific cortical GABA neurotransmission and oscillations in vitroProject 2 investigates the functional properties and receptor subtypes mediating transmission at the inhibitory synaptic connections made by specific classes of GABA neurons in local circuits of the primate neocortex. The studies are motivated by the hypothesis that the presence of short- versus long-lasting inhibitory postsynaptic currents (IPSCs) at specific connections in the cortical network may associate the activity of certain interneuron subclasses with high (gamma, 30-80Hz) and low (theta, 4-8 Hz) frequency oscillations, respectively. Specifically, we suggest that fast spiking (FS) and non-fast-spiking (nFS) neurons signal via fast and slow IPSCs, respectively. In addition, we hypothesize that different subtypes of ionotropic GABA-A receptors underlie the fast and slow IPSCs in connections from FS and nFS neurons. In computational modeling studies, we will test the validity of the idea that fast and slow IPSCs may associate FS and nFS neurons with gamma and theta network oscillations. Electrophysiological studies in vitro will determine whether indeed FS and nFS neurons signal via fast and slow IPSCs. In addition, the subtypes of GABA-A receptors mediating the IPSCs at connections made by FS and nFS onto other cells of the neocortical network will be assessed using novel benzodiazepine-like compounds that act in a receptor subtype-selective manner. These investigations will be supported by quantitative anatomical studies of the subtype of GABA-A receptor at the different types of synaptic connections using immunocytochemical labeling and fluorescence microscopy techniques. The data obtained in the computer simulations and electrophysiological studies will be integrated in order to build a biophysically-based model of the neocortical network in which the effects of manipulating receptor subtypes is simulated. In light of the previously described alterations in GABA neurons and GABA-A receptor subtypes in schizophrenia, the studies in Project 2 will not only increase our understanding of interneuron function and dysfunction in the illness, but may also have predictive value in terms of future pharmacological interventions based on GABA-A receptor subtypes.
Project 3 - The role of GABA neurotransmission in cortical oscillations elicited by tasks that tap in non-human primates the same information processing domains that are altered in schizophreniaAll research in this Center is directed at testing a general hypothesis concerning the origin of the information processing deficits of schizophrenia. The hypothesis states that molecular alterations among GABA neurons give rise to abnormalities of cerebral cortical oscillatory activity and that abnormal oscillatory activity gives rise to impaired information processing. Testing this hypothesis will lead to an improved understanding of the pathophysiological mechanisms that underlie impaired information processing in schizophrenia and will thereby pave the way to the development of novel, mechanistically-based treatments. Project 3 will contribute to the attainment of the goals of the Center by characterizing cognition-related oscillatory activity in the cerebral cortex of behaving monkeys. Experiments conducted under Aim 1 will focus on gamma-band (30-80 Hz) oscillations in frontal cortex that accompany the preparation to overcome a prepotent response. Experiments conducted under Aim 2 will focus on gamma-band oscillations in occipitotemporal cortex that accompany selective visual attention. Experiments conducted under Aim 3 will focus on theta-band (4-8 Hz) oscillations in occipitotemporal cortex evoked by displays consisting of a central and a peripheral visual stimulus. In each experiment, oscillatory activity will be examined at multiple levels of spatial resolution (dural surface potential, local field potential and action potential). In each experiment, the dependence of oscillatory activity on GABA neurotransmission will be assessed by measuring the impact of locally administered agents that exert a potentiating (benzodiazepine) or blocking (GABA antagonist) effect at GABA-A receptors. In each experiment, three fundamental hypotheses will be tested: (1) that the amplitude of oscillatory activity depends on the task conditions; (2) that oscillatory activity recorded at an intracranial site is correlated with oscillatory activity recorded at the overlying cortical surface; (3) that oscillatory activity depends on GABA neurotransmission. By improving our understanding (a) of how cortical oscillatory activity recorded at the brain surface is related to intracranial oscillatory activity and (b) of how intracranial oscillatory activity depends on GABA, the results will increase our understanding of the neural mechanisms that underlie scalp-recorded oscillatory activity in healthy subjects. This will form a basis for drawing inferences about the pathophysiological mechanisms that underlie abnormal cognition-related oscillatory activity in schizophrenia. An understanding of the pathophysiology will form a foundation for the development of novel mechanistically based treatments aimed at ameliorating the cognitive impairments of schizophrenia.
Project 4 - Specific types of information processing disturbances in schizophrenia that are linked to altered activation of, and impaired network oscillations in, certain cortical regions Cognitive and other information processing impairments are a prominent, disabling feature of schizophrenia and a strong predictor of functional outcome. Thus, understanding the pathophysiologic mechanisms underlying these deficits has become a critical focus in the development of novel therapeutics for the illness. A central hypothesis of the Center is that disturbances in GABA neurotransmission are a neurobiological substrate for these deficits by virtue of their role in generating and sustaining the synchronous oscillations in cortical networks that appear to be critical for various cognitive processes. In this project, we will investigate oscillatory disturbances in first-episode, antipsychotic-naïve individuals with schizophrenia (FEAN-S). We will also study first-episode, antipsychotic-naïve, non-schizophrenia psychotic (FEAN-NS) subjects to permit a systematic investigation of the diagnostic specificity of our findings. We will employ a multimodal imaging approach, including EEG and fMRI. EEG measures will be used to assess disturbances in gamma (30-80 Hz) and theta (4-8 Hz) oscillations, using task paradigms and examining brain regions that are effective tests of disturbances in oscillations at these two frequency bands. Closely analogous EEG tasks will be employed in monkeys in Project 4, but with measures of neural circuit functioning at a much finer physiologic resolution, thus allowing more detailed assessment of oscillatory dynamics, including their sensitivity to pharmacologic manipulations of GABA neurotransmission. Using the same task paradigms, fMRI measures will provide an index of local cortical circuit activity and thus provide critical information regarding the anatomic distribution of findings. Project-5 will provide in vivo PET measures of GABA neurotransmission in a subset of the same subjects, thus permitting inferences concerning the dependence of EEG and fMRI findings on GABA neurotransmission. Studying FEAN-S subjects will permit an evaluation of the extent to which oscillatory disturbances are a core pathophysiologic finding present early in the illness, in the absence of possible treatment effects, and will provide the basis for potential generalization of findings to the schizophrenia population at large. This project, together with other projects in the Center, could lead to a rich convergence of findings with the potential to provide biomarkers important in novel therapeutics development in schizophrenia.
Project 5 - The development of new PET imaging tools for studying the function of human cortical GABA neurons in vivoOne of the most consistent and replicated postmortem findings in schizophrenia is the reduced expression of the mRNA encoding the 67 kD isoform of glutamic acid decarboxylase (GAD67), the enzyme principally responsible for the synthesis of GABA. A central hypothesis of the Center is that disturbances in GABA neurotransmission play a key role in the information processing impairments observed in schizophrenia. These impairments represent a prominent and disabling feature of schizophrenia and a strong predictor of functional outcome. Thus, understanding the pathophysiologic mechanisms underlying cognitive impairments has become a critical focus in the development of novel therapeutics for the illness. However, to date, there is no direct, in vivo evidence that GABA function is altered in schizophrenia or that the GABA abnormalities observed in postmortem studies are linked to functional impairments in this illness. Consequently, the goal of this project is to develop and validate a methodology for exploring, in vivo, the evidence that GABA transmission is broadly impaired, across cortical brain regions, in subjects with schizophrenia. This project will (1) validate the use of [11C]flumazenil PET to detect changes in extracellular GABA levels resulting from the administration of tiagabine (a drug which inhibits the reuptake of GABA by blocking the GABA transporter, GAT1) and (2) examine tiagabine-induced changes in GABA levels in cortical regions in first-episode, antipsychotic-naïve, schizophrenia subjects (FEAN-S) compared with healthy controls. We predict that schizophrenia will be associated with a deficit in the ability to increase extracellular GABA levels in response to tiagabine when measured in vivo, using PET. All subjects will participate in Project 4 which will create a multi-modal dataset permitting us to explore the existence of a number of relationships predicted by the overall model of this Center. We will test the hypothesis that, in FEAN-S subjects, deficits in the ability to increase GABA levels, as indicated by blunting of the change in [11C]flumazenil binding in response to tiagabine, will be associated with impaired gamma oscillatory activity as measured by EEG, and decreased fMRI BOLD signal, during a cognitive control task, and that the level of cognitive impairment will be inversely correlated with the ability to increase GABA levels. This project will provide a key link between the postmortem studies of Project 1 and the clinical studies outlined in Project 4. It will allow us to directly test the hypothesis that GABA transmission is reduced in schizophrenia (Project 1) and, in combination with data from Project 4, determine if reduced GABA is associated with the oscillation and fMRI disturbances observed in vivo. The methods developed through this project will thus provide an innovative biomarker that can be used to monitor the effects of novel therapeutic drugs in schizophrenia.
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Corrie Long