Npas4 regulates medium spiny neuron physiology and gates cocaine‐induced hyperlocomotion

Abstract

We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine‐induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA‐stimulating input, in mouse medium spiny neurons and human iPSC‐derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired‐pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged.

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

“…In pyramidal neurons, it is reported to enhance inhibitory synaptic transmission, while in somatostatin-positive interneurons, it augments excitatory synaptic transmission 33,[35][36][37][39][40][41][42] ; however, the role of NPAS4 in regulating striatal circuits and SUD-related plasticity and behavior is poorly understood. NPAS4 is induced rapidly and transiently in a small subset of NAc neurons during cocaine conditioning, and its NAc expression is required for cocaine CPP 43 and cocaine locomotor sensitization 44 , but also see data herein and 43 . Therefore, investigating the role of NAc NPAS4 in promoting drug-seeking behaviors and maintaining the D1/D2 activity balance addresses a significant knowledge gap.…”

Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder

“…It should be highlighted that the larger change observed in DLPFC can also be attributed to its larger sample size. It has been previously demonstrated that NPAS4 plays a role in memory (Sun & Lin, 2016), modulating inhibitory-excitatory balance (Lin et al, 2008; Opsomer et al, 2020; Spiegel et al, 2014), epileptogenesis in mice, cocaine-induced hyperlocomotion (Lissek et al, 2021), cognitive well-being and many other diseases (Coutellier et al, 2012; Fu et al, 2020; Funahashi et al, 2019; Maya-Vetencourt, 2013). While the association between NPAS4 and MDD has been shown in mice previously (Jaehne et al, 2015), we validated the same relationship for humans and multiple brain regions.…”

The Universal Role of Adaptive Transcription in Health and Disease

“…DeltaFosb, an alternative splice variant of Fosb, regulates cocaine-induced locomotor behavior [129] and reward [123]. Npas4 controls several parameters of medium spiny neuron physiology and cocaine-induced locomotor responses [130], as well as conditioned place preference [131].…”

“…They also oftentimes allow the conceptual bridging of organizational levels in that molecular alterations have defined effects on tissue organization which in turn leads to differences in organism function and behavior. An example is Npas4's dependency on cellular input [130,230], subsequent cell-type specific remodeling [35,130] and then specific influence on behavior [34,130].…”