GABAergic synapses are the major inhibitory connections in the brain and likely play an important role in all brain functions, including learning and memory. A deficit in GABAergic synapses is often implicated in devastating disorders such as autism, schizophrenia, and epilepsy. Despite their importance, many fundamental questions regarding the regulation and function of GABAergic synapses remain unanswered. Our long-term goal is to explore the cellular and molecular mechanisms by which neuronal activity is coupled to modification of GABAergic synapses during behavioral experience and to understand how disruption of this form of GABAergic synaptic plasticity leads to cognitive deficits. Towards this goal, we have recently identified the activity-regulated bHLH-PAS transcription factor Npas4 as a key regulator of GABAergic synapses. Npas4 is rapidly induced by excitatory synaptic activity and its level determines the number of GABAergic synapses formed on excitatory neurons. These findings suggest that Npas4 is the molecular link between neuronal excitation and GABAergic synapses. By investigating Npas4's role in regulating activity-dependent modulation of GABAergic synapses and regulating behavioral output of neural circuits, the research plan outlined here will yield new insights into the etiology of many neurological disorders.
The research described in this proposal will explore the role of GABAergic synaptic plasticity in important neural circuit functions such as learning and memory. A deficit in GABAergic synapses is often implicated in devastating neurological disorders such as autism, schizophrenia, and epilepsy, most of which often involve profound psychiatric and cognitive deficits in afflicted individuals. Our proposed study will shed light on the pathology and etiology of these neurological diseases.
|Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano et al. (2018) Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation. Neuron 97:1137-1152.e5|
|Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6|
|Sun, Xiaochen; Lin, Yingxi (2016) Npas4: Linking Neuronal Activity to Memory. Trends Neurosci 39:264-275|
|Sørensen, Andreas T; Cooper, Yonatan A; Baratta, Michael V et al. (2016) A robust activity marking system for exploring active neuronal ensembles. Elife 5:|
|Chuong, Amy S; Miri, Mitra L; Busskamp, Volker et al. (2014) Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 17:1123-9|
|Leong, Wai Khay; Klaric, Thomas S; Lin, Yingxi et al. (2013) Upregulation of the neuronal Per-Arnt-Sim domain protein 4 (Npas4) in the rat corticolimbic system following focal cerebral ischemia. Eur J Neurosci 37:1875-84|
|Sim, Shuyin; Antolin, Salome; Lin, Chia-Wei et al. (2013) Increased cell-intrinsic excitability induces synaptic changes in new neurons in the adult dentate gyrus that require Npas4. J Neurosci 33:7928-40|
|Ramamoorthi, Kartik; Fropf, Robin; Belfort, Gabriel M et al. (2011) Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334:1669-75|
|Ramamoorthi, Kartik; Lin, Yingxi (2011) The contribution of GABAergic dysfunction to neurodevelopmental disorders. Trends Mol Med 17:452-62|