Our research walks the thin line between psychology and biology. We use molecular biology tools to manipulate neural circuits in rats and mice, and ask questions from the field of experimental psychology - how learning is affected, what is the impact on memory and attention, and how affect is changed.
Animal models of abnormal glutamate transmission in schizophrenia
One out of every hundred people worldwide suffers from schizophrenia (SZ), a brain disorder characterized by debilitating symptoms that affect perception, cognition and affect. Glutamate abnormalities have been extensively reported in SZ, although the precise nature and directionality of these abnormalities remains unclear.
We study mice that are genetically modified to express abnormal levels of proteins involved in glutamate metabolism. We have shown that mice with a specific mutation in the gene that encodes the glutamate-recycling enzyme glutaminase (GLS1; Fig. 1) show a phenotype of resilience to some of the core phenotypes in SZ. For example, while excessive amounts of dopamine are released in the striatum of schizophrenia patients in response to the pro-psychotic drug amphetamine, this response is attenuated in mice heterozygous for a mutation in the GLS1 gene (GLS1 hets), and these mice also display an antipsychotic-like profile in the latent inhibition model, and a hippocampal activation profile opposite to that see in patients with schizophrenia and prodromal subjects (Fig 2). In collaboration with Profs Stephen Rayport and Scott Small (Columbia University), we are further characterizing these mice, and studying them in light of principal neurodevelopmental and genetic theories of SZ. Furthermore, we are using genetic and molecular techniques (e.g. selective breeding, injection of lentiviruses) to limit glutaminase deficiency to particular brain regions and developmental time frames. We use a variety of behavioral assays – locomotion in an open field, fear conditioning, latent inhibition, working memory tasks, novel object recognition and others – to phenotype the mice.
Since our findings in GLS1 het mice indicate that reduced hippocampal glutamate may be beneficial for treatment of SZ, we are also phenotyping mice with enhanced levels of hippocampal glutamate, with the expectation that some behavioral and neurochemical features of SZ will be present.
The overall goal of these studies is to better understand the involvement of glutamate in schizophrenia so that new venues of treatment can be developed.
Epigenetic mechanisms contributing to cognitive function and affective states
Behavior is influenced by “nature” - the genetic code passed down to us from our parents- and by “nurture” the experiences that affect us on a daily basis. One idea that has emerged in recent years is that our genetic code may be influenced by environmental factors, such as diet or stress. Several epigenetic mechanisms can explain the modification of the genetic code as a result of environmental stimuli – DNA methylation, alternative splicing of genes, and histone modification, for example. In our lab, we focus on RNA editing, an epigenetic process whereby adenosine (A) within the pre-mRNA sequence is converted to inosine (I) in specific locations by enzymes belonging to the Adenosines Acting on RNA (ADAR) family of enzymes. When this specific editing occurs within a coding region, it has the potential to alter codon specificity because the ribosome reads inosine as guanosine and, as a result, amino acid sequence and protein function may be altered. When editing occurs in non-coding regions, i.e. in untranslated regions or introns, it may affect secondary structures and influence splicing, translational efficiency or other processes involving protein binding.
Recent Studies using combined computational and molecular biology techniques show that RNA editing is particularly relevant to brain function and psychiatric disorders, due in a large part to the regulation via editing of the activities of neurotransmitter receptors and ion channels, including the iontotropic glutamate receptors (GluRs), Kv1.1 potassium channel and the serotonin receptor 2C. (Fig 3).
In our lab, we ask how periods of intense learning or mild stress affect editing, directly and indirectly. In collaboration with Prof. Micah Leshem (U of Haifa), we are exploring the epigenetic basis of trans-generational transmission of stress effects. In a second project, we examine the effects of hippocampus-dependent learning on editing saturation at the AMPA GluR2 Q/R site. For these projects, we use a variety of tools such as behavioral analysis, cDNA sequencing, and RT-PCR.
Ultimately, we hope that these studies will help us better understand the interaction between genes and environment in relevance to psychiatric disease.