Several lines of evidence indicate that fast excitatory transmission mediated by AMPA receptors regulates expression of BDNF. As predicted from this, increasing the size of excitatory postsynaptic currents with positive modulators of AMPA receptors (ampakines) increases BDNF expression both in cultured brain slices and in vivo. These results raise the possibility of using AMPA receptor modulators to produce sustained increases in the brain's concentration of a critical trophic factor. However, preliminary studies using a novel cultured slice technique for 'chronic' recording of synaptic responses led to the discovery that ampakines depress excitatory responses after about 24-36 hours. Follow on experiments showed that the depression is accompanied by a marked reduction in the number of AMPA receptors in membrane fractions. Separate work in the laboratory of Dr. Gall uncovered a parallel effect with regard to BDNF induction: prolonged exposure causes cultured slices to become refractory to ampakines. The proposed work has five objectives relating to these findings.
Specific Aim One will define the time course for the onset of, and recovery from, EPSP depression. This information will be compared to the temporal parameters of the BDNF refractory period (see Project One).
Specific Aim Two will test the hypothesis that down-regulation of AMPA receptors is responsible for EPSP depression. Number and affinity of the membrane receptors will be measured first; subsequent work will assay for changes in levels of receptor subunits and turnover.
Specific Aim Three addresses additional mechanistic questions relating to EPSP depression: What are the triggering events? Are signaling pathways linking AMPA receptor activation to AMPA receptor regulation and BDNF expression disturbed? (Also see Project One).
Specific Aim Four investigates the functional consequences of AMPA receptor down-regulation. Long term potentiation, long term depression, and seizure susceptibility will be tested prior to and after the onset of the effect. Studies on how LTP is affected by ampakine-induced elevation of BDNF in the absence of depression are described in Project Three.
Specific Aim Five will test for the occurrence of AMPA receptor down-regulation and signaling in vivo. In all, the results of the proposed study are expected to yield new and fundamental information concerning AMPA receptor regulation. They are also expected to be critical in the development of an AMPA receptor based strategy for up-regulating a critical trophic factor.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
United States
Zip Code
Wang, Weisheng; Le, Aliza A; Hou, Bowen et al. (2018) Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus. J Neurosci 38:7935-7951
Wang, W; Cox, B M; Jia, Y et al. (2018) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23:1798-1806
Wang, Yubin; Hall, Randy A; Lee, Moses et al. (2017) The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation. Sci Rep 7:11771
Cox, Conor D; Palmer, Linda C; Pham, Danielle T et al. (2017) Experiential learning in rodents: past experience enables rapid learning and localized encoding in hippocampus. Learn Mem 24:569-579
Prieto, G Aleph; Trieu, Brian H; Dang, Cindy T et al. (2017) Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses. J Neurosci 37:1197-1212
Zhu, Guoqi; Briz, Victor; Seinfeld, Jeff et al. (2017) Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Sci Rep 7:42788
Wang, Yubin; Lopez, Dulce; Davey, Pinakin Gunvant et al. (2016) Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury. Neurobiol Dis 93:121-8
Seinfeld, Jeff; Baudry, Neema; Xu, Xiaobo et al. (2016) Differential Activation of Calpain-1 and Calpain-2 following Kainate-Induced Seizure Activity in Rats and Mice. eNeuro 3:
Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C et al. (2016) Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses. J Neurosci 36:11295-11307
Wang, Yubin; Hersheson, Joshua; Lopez, Dulce et al. (2016) Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. Cell Rep 16:79-91

Showing the most recent 10 out of 100 publications