The cerebellum is critically involved in motor coordination and associative learning, both of which are regulated by stress. Stress can trigger cerebellar ataxia in susceptible individuals and also enhances associative learning. We have recently shown that noradrenaline released during an acute olfactory stress in mice promotes GluR2 gene transcription and alters excitatory synaptic transmission onto cerebellar inhibitory interneurons. In addition we found that this stress-induced increase in synaptic GluR2 expression has important consequences because it markedly enhances the activity of cerebellar stellate cells. These inhibitory interneurons alter Purkinje cell firing, and thereby control motor coordination and learning. Therefore we propose that stress enhances GluR2 gene transcription and consequently alters learning-induced synaptic plasticity. This provides a novel mechanism by which stress can regulate associative learning and memory. The primary objective in this proposal is to understand the mechanisms and functional consequences of this stress-induced transcriptional dependent switch. Our central hypothesis is that the stress hormone, noradrenaline, increases the number of synaptic GluR2-containing receptors via epigenetic remodeling of the GluR2 gene, thereby altering the synaptic plasticity that is induced by associative learning.
The specific aims are:
Aim 1. To determine the underlying mechanisms for the stress-induced increase in GluR2 gene transcription in stellate cells. We will examine the role of two transcriptional regulators. 1) The transcriptional activator CREB which promotes GluR2 transcription. We will test whether noradrenaline promotes GluR2 transcription via activation of cAMP/PKA/CREB signaling pathways. 2) The transcriptional repressor REST binds to the GluR2 promoter region and recruits histone deacetylases which can silence GluR2 gene expression. We test the hypothesis that stress acts via chromatin remodeling to increase GluR2 mRNA.
Aim 2. To examine the consequences of a stress-induced enhancement of GluR2 transcription on learning-dependent synaptic plasticity. We will test the prediction that stress enhances associative learning-dependent synaptic plasticity and attenuates the extinction-induced reversal in stellate cells. The proposed study is designed to determine how a stress-induced change in interneuron functioning can alter the synaptic plasticity that is observed during learning. It may also provide insights into how stress can act as a trigger for cerebellar ataxias. Alterations in GluR2 gene transcription contribute to a number of neurological disorders, including stress-induced depression and ischemia-induced neuronal death. Findings from the proposed studies are relevant to our understanding of many stress-related neurological disorders.
Stress can cause mental illnesses, such as depression and anxiety disorders and can trigger cerebellar ataxia. Stress is known to enhance associative learning and has been implicated in the development of post-traumatic stress disorders. Our investigation of the stress-induced change in synaptic AMPA receptors could contribute to our understanding of the cellular mechanisms underlying stress-related memory and has implications for the neurological disorders that are associated with changes in GluR2 gene transcription, such as depression and epileptic seizures.
|Bender, Crhistian L; Yang, Qian; Sun, Lu et al. (2016) NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. Neuropharmacology 101:531-7|
|Dubois, Christophe J; Lachamp, Philippe M; Sun, Lu et al. (2016) Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release. J Neurophysiol 115:271-85|
|Savtchouk, Iaroslav; Sun, Lu; Bender, Crhistian L et al. (2016) Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3. Cell Rep 17:86-103|