Jerri M. Rook, Ph.D. - US grants

DESCRIPTION (provided by applicant): Preclinical and clinical studies suggest that ligands for metabotropic glutamate receptors (mGluR5) have exciting potential for treatment of a wide variety of neurological and psychiatric disorders, including depression, anxiety disorders, schizophrenia, pain, epilepsy, Alzheimer's disease, and Fragile X syndrome. Dr. Conn's laboratory and others have been highly successful in developing a novel approach to the activation of mGluR5 using highly selective positive allosteric modulators (PAMs) of this receptor. These mGluR5 potentiators do not activate the mGluR5 receptor directly, but dramatically potentiate the response to the orthosteric ligand glutamate. mGluR5 allosteric modulators have exciting potential as novel therapeutic agents and are being rapidly advanced in preclinical and early clinical drug development efforts. Recent studies in Dr. Conn's laboratory suggest that PAMs of the mGluR5 may provide a novel approach for the treatment of the psychotic symptoms and cognitive impairments observed in individuals with schizophrenia. Additionally, mGluR5 receptors have been implicated in the cognitive deficits observed in individuals with fragile X syndrome. This proposal involves determining the functional brain penetrance and in vivo efficacy of the novel selective mGluR5 PAM, VU0357040. In the initial studies, we will determine the in vivo receptor occupancy of VU0357040 via microPET imaging utilizing the radioligand [ISFJFPEB in order to understand the functional brain penetrance of this compound. Based on these occupancy studies, we will select doses and timepoints for further characterization of VU0357040 in behavioral models predictive of antipsychotic activity and enhancement of cognition. Specifically we will assess the ability of VU0357040 to reverse stimulant-induced disruptions in prepulse inhibition of the acoustic startle reflex, a model of antipsychotic efficacy and sensory gating enhancement. In addition we will assess the effects of this compound in the delayed non-matching to position task, a model of working memory. Finally, using animal models of hippocampal-dependent learning and memory, namely the Morris water maze task and contexual fear conditioning, we will evaluate the effects of this mGluR5 PAM on cognitive function in an animal model of fragile X syndrome. Ultimately, a better understanding of allosteric activation of these receptors may lead to improved therapies for patients suffering from a variety of psychiatric and neurological disorders.

? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most frequently observed cause of dementia and cognitive decline associated with neurodegeneration. Current therapies provide modest improvement in cognitive function in some patients, while providing no efficacy in others. Glutamate is the primary excitatory neurotransmitter of the central nervous system and glutamatergic transmission is severely disrupted in AD and other neurodegenerative disorders. Among the principle cognitive deficits associated with AD are deficiencies in hippocampal-mediated learning and memory. Glutamatergic neurotransmission is critical in hippocampal synaptic plasticity and hippocampal-dependent cognitive function and accumulating evidence suggests that enhancement of glutamatergic neurotransmission could help to reverse cognitive deficits associated with AD. In recent years, a specific subtype of metabotropic glutamate (mGlu) receptor, termed mGlu5, has emerged as an exciting target for new therapeutic agents that could be used to reduce impaired cognitive function in patients suffering from AD and other neurodegenerative disorders. The mGlu5 receptor is the most highly expressed mGlu receptor subtype in the hippocampus and cortical regions that are impacted in AD patients, and plays a major role in the regulation of forms of synaptic plasticity that are believed to underlie learning and memory and other aspects of cognitive function. Furthermore, activation of mGlu5 can induce non-pathologic processing of amyloid precursor protein (APP) to reduce brain levels of A?. Interestingly, evidence suggests that mGlu5 signaling is impaired in tissue from AD patients. These studies raise the exciting possibility that highly selective activators of mGlu5 could provide a novel approach to reverse the cognitive impairments and reduce some of the pathophysiological changes that are associated with AD. While initial attempts to develop selective orthosteric agonists of individual mGlu receptor subtypes were unsuccessful, we and others have been highly successful in discovery of selective positive allosteric modulators (PAMs) for mGlu5. These PAMs do not activate the mGlu receptors directly but potentiate glutamate-induced activation, thus preserving spatio-temporal signaling of the endogenous ligand. We now propose a series of studies aimed at fully characterizing the in vivo efficacy of mGlu5 PAMs to restore deficits in synaptic and cognitive function in the CK-p25 mouse model of AD. CK- p25 mice provide a preclinical model of AD that displays a number of pathological features that bear a striking similarity to those observed in AD patients, including neurodegeneration, increased tau phosphorylation and neurofibrillary tangles, elevated amyloid-beta protein (A?) and the amyloid precursor protein (APP) processing enzyme, ?-secretase (BACE1), as well as pronounced deficits in synaptic and cognitive function. This provides an excellent model that is well suited for testing the hypothesis that mGlu5 PAM will have efficacy in improving synaptic plasticity, cognitive function, and other pathological changes that are characteristic of human AD and neurodegenerative disorders.