Schizophrenia is the 7th most costly illness to Society because of the lack of drugs to effectively treat the persistent negative symptoms and cognitive deficits. These two symptom domains correlate with the degree of cortical atrophy, which results from dendritic atrophy and loss of synapses. We proposed 20 years ago that this pathology resulted from hypofunction of NMDA receptors (R). Recent GWAS and CNV results in schizophrenia have substantiated our hypothesis by demonstrating that risk genes are markedly enriched in ones encoding proteins localized to glutamatergic synapses. During the previous 4 years of support, we have shown that genetic silencing in mice of serine racemase (SR-/-), an established risk gene for schizophrenia and the source of D- serine, the co-agonist at cortical NMDARs, replicates many of the neuropathologic, neurochemical and behavioral features of schizophrenia. Treating the SR-/- mice for 3 weeks with doses of D-serine that restored cortical levels to normal reversed these deficits. We seek three years of additional support to build upon these findings to advance our understanding of the role of SR in psychiatric disease and to determine whether the deficits due to the NMDAR hypofunction endophenotype of schizophrenia can be pharmacologically reversed.
Aim 1. What is D-serine doing in cortical GABAergic interneurons? We were surprised to discover that astrocytes do not express SR or D-serine but that over half of the cortical cells containing D-serine are GABAergic neurons. Having successfully crossed SRfl/fl mice with mice with Cre driven by a GAD65 promoter, we will determine how the suppression of SR expression only in GABAergic neurons affects their electrophysiology, D-serine distribution and behavior.
Aim 2. Can D-serine deficiency be overcome by heteroreceptor pharmacologic interventions? We will examine the efficacy of a positive allosteric modulator for the mGluR5 receptor, which enhances NMDAR function, and a positive allosteric modulator for the alpha-7 nicotinic receptors, which are concentrated on PV+GABAergic neurons and promote glutamate release, in reversing neurochemical, behavioral, electrophysiologic and dendritic deficits in SR-/-.
Aim 3. Does SR induced in reactive astrocytes contribute to symptoms? Inflammation is an important feature of the pathology of schizophrenia, correlating with the deficit state. Recently, we found that reactive astrocytes express SR and D- serine. We hypothesize that D-serine released by reactive astrocytes activates extra-synaptic NMDARs, contributing to cognitive deficits and negative (depressive-like) symptoms. We will characterize the expression of SR and D-serine and the transporter, Asc-1, in tissue culture and in a model of reactive astrocytosis: systemic LPS treatment. We will determine whether the behavioral phenotype is reduced in astrocyteSR-/- mice after LPS treatment and whether LPS exacerbates the phenotype in neuronalSR-/- mice.
We have demonstrated that inactivating in mice the gene for serine racemase, a risk gene for schizophrenia that synthesizes D-serine, the co-agonist at cortical NMDA receptors, replicates many of the neurochemical, structural and cognitive features of schizophrenia. We propose clarifying the role of serine racemase in cortical GABAergic neurons and reactive astrocytes and determining whether pharmacologic interventions that enhance NMDA receptor or alpha7 nicotinic receptor function can reverse the deficits, which are linked to persistent negative symptoms and cognitive impairments in schizophrenia.
Showing the most recent 10 out of 62 publications
