Research SummarymGluR-Dependent Synaptic Plasticity: Parallels and Distinctions between the Hippocampus and Amygdala and Implications for Fragile X Syndrome
Fragile X syndrome (FXS) is the leading heritable cause of intellectual disability and autism, caused by transcriptional silencing of the Fmr1 gene and consequent loss of expression of the FMRP protein.
Since moderate to severe mental retardation is a key characteristic of FXS, earlier studies have mostly been biased towards understanding the synaptic basis of hippocampal and cortical dysfunction. However, patients also display highly debilitating emotional pathologies, including anxiety, hyperarousal and social avoidance, likely encoded by another brain area called the amygdala. My work will compare aspects of hippocampal and amygdalar synaptic plasticity that are directly relevant to the cognitive and affective symptoms of FXS.
Type-5 metabotropic glutamate receptor (mGluR5) activation in hippocampal slices leads to long-term depression of synaptic responses. Surprisingly, the same treatment leads to strengthening of synapses in the amygdala. Therefore, the first goal of my proposal aims to elucidate mechanisms underlying mGluR5 mediated, contrasting patterns of synaptic plasticity in the hippocampus and amygdala.
Furthermore, in the Fmr1-KO mouse model of FXS, hippocampal mGluR-LTD is enhanced while amygdalarmGluR-LTP is impaired, potentially sub-served by excessive mGluR5-dependent postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptor (AMPAR) internalization in both the brain regions. Thus, the second goal of my proposal aims to investigate mGluR5-dependent AMPAR trafficking deficits in Fmr1-KO mice.
Figure Legend: Contrasting patterns of mGluR dependent synaptic plasticity in the hippocampus and amygdala (left) and the associated changes in Fmr1-KO mice (right).