Scientific Understanding of Consciousness
Activity-Dependent Tanscription Factor
Nature 503, 121–125 (07 November 2013)
The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
Brenda L. Bloodgood, Nikhil Sharma, Heidi Adlman Browne, Alissa Z. Trepman & Michael E. Greenberg
Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA
Brenda L. Bloodgood
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA; Department of Neuroscience, Brown University, National Institutes of Health Graduate Partnership Program, Providence, Rhode Island 02912, USA
Heidi Adlman Browne & Alissa Z. Trepman
A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinates the redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.
These findings indicate that when a mouse engages with its environment, the neuronal activity-regulated transcription factor NPAS4 is expressed in pyramidal neurons of the hippocampus where it promotes an increase in the number of inhibitory synapses on the cell soma and a decrease in the number of inhibitory synapses on the apical dendrites. In light of recent reports indicating that inhibition within these cellular domains can have distinct functions, we speculate that this redistribution of inhibition will have significant effects on information processing in the postsynaptic neuron. For example, the opposing regulation of somatic and apical dendritic inhibition may allow integration or plasticity of excitatory events in the apical dendrites while still limiting the generation of somatic action potentials and thus the propagation of information to downstream neurons. This is in contrast to homeostatic scaling of inhibitory synapses—a process whereby the action potential output of a neuron is regulated by cell-wide scaling of synaptic strengths that preserves the relative strengths among synapses. The NPAS4-dependent redistribution of inhibitory circuitry may underlie recent findings that associate NPAS4 function with contextual or stimulus dependent fear conditioning.
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