ABSTRACT
Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.
Subject(s)
Brain-Derived Neurotrophic Factor/physiology , Gene Expression Regulation , Glutamate Decarboxylase/biosynthesis , Signal Transduction/physiology , Animals , Benzylamines/pharmacology , Bicuculline/pharmacology , Butadienes/pharmacology , Calcium Signaling/drug effects , Carbazoles/pharmacology , Cells, Cultured , Cerebral Cortex/cytology , Enzyme Induction/drug effects , GABAergic Neurons/drug effects , GABAergic Neurons/enzymology , GABAergic Neurons/metabolism , Gene Expression Regulation/drug effects , Glutamate Decarboxylase/genetics , Homeostasis , Indole Alkaloids/pharmacology , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred ICR , Nitriles/pharmacology , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, trkB/antagonists & inhibitors , Receptor, trkB/physiology , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/physiology , Signal Transduction/drug effects , Sulfonamides/pharmacology , gamma-Aminobutyric Acid/metabolismABSTRACT
The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.
