Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4

Abstract

Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or if a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in these neurons’ input synapses, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter a neuron’s synaptic connectivity with the hippocampal circuit, and that Npas4 is required for activity-dependent changes in input synapses.

Npas4: Linking Neuronal Activity to Memory

“…In adult-born dentate gyrus granule neurons, Npas4 has been found to be a major mediator of the effect of neural activity on both the GABAergic and glutamatergic synaptic inputs the neurons receive: increasing the excitability of individual newborn neurons significantly altered their GABAergic synaptic inputs and dendritic spines (the sites of the majority of glutamatergic synapses), and these effects were completely abolished by deleting the Npas4 gene [8]. In adult-born olfactory bulb granule cells (OBGCs), which are GABAergic, Npas4 is induced by odorant exposure and is required for dendritic spine formation in these cells following the sensory experience [9].…”

“…BDNF was subsequently shown to be required only for the activity-dependent up-regulation of perisomatic inhibitory synapses on CA1 pyramidal neurons that is mediated by Npas4, but not for its down-regulation of dendritic inhibitory synapses [37]. Surprisingly, BDNF was not involved in the activity-dependent modulation of either GABAergic or glutamatergic synapses on adult-born dentate gyrus granule neurons, which requires Npas4 [8]. In adult-born OBGCs, Npas4 regulates dendritic spine density through the E3-ubiquitin ligase murine double minute 2 (Mdm2) [9].…”

The balancing act of GABAergic synapse organizers

“…Neuronal PAS domain protein 4 (Npas4) is a transcription factor encoded by a neuronal activity-dependent immediate-early gene and is required for activity-dependent inhibitory synapse development, activity-dependent changes in inhibitory synaptic connectivity, and neurite outgrowth [62][63][64]. Npas4 knockdown selectively reduces the number of inhibitory synapses formed on both the soma and dendrites, suggesting that Npas4 may regulate the development of inhibitory synapses originating from multiple interneurons [62].…”

Region-specific regulation of voltage-gated intrinsic currents in the developing optic tectum of theXenopustadpole

“…So, at least the ability to fire repetitively appears to be enhanced in tectal neurons expressing relatively big K ϩ currents. It has been well established that the way a neuron functions as part of a circuit is shaped by the complement of intrinsic currents it expresses (Bean 2007;Connors et al 1982;Marder 2011;Sim et al 2013;Turrigiano et al 1996). In turn, alterations in the amount or pattern of circuit activity (spontaneous or sensory driven) received by an individual neuron can shape the expression of its intrinsic currents (Aizenman et al 2003;Aizenman and Linden 2000;Baines et al 2001;Cudmore et al 2010;Desai et al 1999b;Driscoll et al 2013;Turrigiano et al 1994).…”