|The endocannabinoid system in a mouse model of Fragile X Syndrome
by Bradley E. Alger, 5/1/2011
Photo: Ai-Hui Tang and Bradley Alger
Regulation of GABAergic synaptic inhibition is a critical factor in normal brain development and functioning. Dysregulation of inhibition in the brain leads to abnormalities in neuronal migration and circuit formation, synaptic connectivity, excitability control, and synaptic plasticity. Decreases in inhibition can cause seizure disorders, such as epilepsy, and are implicated in neurological diseases, such as autism spectrum disorders (ASDs), including Fragile X Syndrome (FXS). Decreased release of GABA is a common way in which GABA inhibition is reduced. Endogenous ligands for the cannabinoid receptor of the brain (CB1R), endocannabinoids (eCBs), are powerful and ubiquitous regulators of many GABA synapses. eCB release can be triggered by Ca2+ influx into postsynaptic cells or by the activation of postsynaptic group I metabotropic glutamate receptors (mGluRs). We have found that the strength of synapses made by CB1R-positive GABAergic nerve terminals in hippocampus is strongly depressed by eCB-mediated suppression of GABA release in the Fmr1-/- mouse model of FXS (Zhang and Alger, 2010, J. Neuroscience, 30:5724-9). Interestingly, nearly identical findings were reported at inhibitory synapses in the striatum by an independent group (Maccarrone et al., 2010), demonstrating the mGluR-eCB hyper-functionality is not unique to the hippocampus. Interestingly, an alteration of mGluR-eCB signaling at hippocampal excitatory synapses was reported by yet another group (Roloff et al., 2010), although in that case the coupling between mGluRs and eCBs was diminished. Nevertheless It may be significant that, from a functional point of view, the changes in the eCB system of Fmr1-/- at excitatory and inhibitory synapses are complementary: they both tend to increase CA1 pyramidal cell excitability. The convergence of these disparate ines of evidence on dysregulation of the eCB system in the FXS model is striking. The eCB dysfunction at inhibitory synapses in Fmr1-/- represents a hyper-functionality of the mGluR-dependent eCB system (eCBmGluR) that is in line with the “mGluR theory of Fragile X”.
The central hypothesis of our proposal is that dysregulation of the eCB system is a contributing factor to the neuronal circuit malfunction in Fmr1-/- and possibly FXS. We now propose a specific cellular/molecular model that links group I mGluRs, brain-derived neurotrophic factor (BDNF), the product of the immediate early gene Homer 1a (H1a), and eCBs. This model can account for data developed our lab and others. The objectives of the proposal are to test the model, with the ultimate goal being to identify new potential therapeutic targets for FXS, as well and to assess known candidate FXS therapies for their effects on the processes and targets in the model.
We will compare wild-type (WT) and Fmr1-/- tissue using a combination of electrophysiological recordings multiple-fluorescence confocal microscopy, dual-immunolabeling electron microscopy, and quantitative real-time polymerase chain reaction (qRT-PCR) in hippocampal brain slices, to test predictions of the core hypothesis. Broadly, this project seeks to answer three questions: 1) what is the nature of the alteration in the coupling between mGluR and eCB in Fmr1-/-, 2) how can that alteration be brought about, and 3) how can the molecular players be targeted?
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