Overview

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 the hippocampus

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 are particularly interested in glutamate transmission in the hippocampus, since many studies point to disruptions in the balance between glutamatergic and GABA-ergic transmission in the hippocampus as a driver of psychosis.

We study mice that are genetically modified to express abnormal levels of proteins involved in glutamate metabolism. We are interested in the effects of these manipulations not only on susceptibility, but also on resilience to schizophrenia. We use genetic and molecular techniques (selective breeding, viral-induced manipulations, chemogenetics) to manipulate glutamate levels in a spatially and temporally limited manner. We use a variety of behavioral assays to test baseline and drug-induced locomotor activity, social and cognitive function. We have developed and optimized novel behavioral assays to test behavioral flexibility and attentional cognitive shifting. In addition, we are interested in testing pharmacological compounds that target glutamate transmission, as a novel treatment venue for symptoms of SZ.

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 form of 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.

In our lab, we are interested in the effects of stress and learning on RNA editing.

Furthermore we are exploring the epigenetic basis of trans-generational transmission of stress effects. Several studies (including our own, in collaboration with Prof. Micah Leshem) have shown that the effects of stress can be passed on to subsequent generations. We are investigating the molecular basis of trans-generational effects, and their possible reversal by psychiatric drugs and environmental interventions.

Ultimately, we hope that these studies will help us better understand the interaction between genes and environment in relevance to psychiatric disease.