Upregulation of the neuronal Per‐Arnt‐Sim domain protein 4 (Npas4) in the rat corticolimbic system following focal cerebral ischemia

Abstract

The neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an important transcriptional regulator of synaptic plasticity and cognition. The present study characterises the in vivo neuroanatomical expression pattern of the Npas4 protein in a rat model of focal cerebral ischemia. Animals were subjected to unilateral middle cerebral artery occlusion for 2 h, after which the spatiotemporal and neuronal profiles of Npas4 protein expression were analysed by immunohistochemistry at different time points post-reperfusion. Focal cerebral ischemia induced an early, transient and robust upregulation of Npas4 in a brain region-dependent manner involving predominantly principal neurons. Interestingly, we observed a unique differential induction of Npas4 protein expression in corticolimbic regions of the rat brain that are critically linked to cognition and emotion. These findings suggest that stroke-induced Npas4 upregulation may be involved in a transcriptional regulatory program within the corticolimbic circuitry following an ischemic insult.

Npas4: Linking Neuronal Activity to Memory

“…In vivo , Npas4 is induced in many regions of the brain by physiological [5, 6, 10, 19–22] or pathological stimuli [23–26]. Under CFC, in which mice learn to associate a novel context with aversive stimuli (foot shocks) during a brief training session, Npas4’s expression in the mouse hippocampus was different from that of other well-known IEGs.…”

The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia

“…Of all brain structures, Npas4 is most abundantly expressed in the hippocampus with the highest expression being detected in the pyramidal cell layers of the cornu ammonis (CA1, CA2 and CA3 regions) and the granule cell layer (GCL) of the dentate gyrus (DG) [ 4 , 5 , 6 , 22 ]. In addition, more recent studies have also detected the expression of Npas4 protein in other limbic structures such as the lateral nucleus of the amygdala and components of the basal ganglia, for example the nucleus accumbens and ventral pallidum [ 15 , 21 ]. These observations indicate that Npas4 is a neuronal transcription factor whose expression is enriched in the limbic system.…”

“…Brain structures outside of the limbic system that have lower levels of Npas4 expression include the cortex, striatum, olfactory bulb (OB), cerebellum and hypothalamus [ 5 , 6 , 21 , 47 , 48 ]. In the cortex, expression is highest in layers III and V and is present in the frontal, parietal and entorhinal cortices [ 5 , 6 , 21 , 22 ]. Some species-specific differences in Npas4 expression have been observed in the cerebellum; in the rat cerebellum, Npas4 expression is confined to the Purkinje cell layer, while in the mouse cerebellum, Npas4 is expressed in both the GCL and the Purkinje cell layer [ 5 , 6 ].…”

“…Due to its central role in homeostasis of neuronal excitation and inhibition, Npas4 has been implicated in a host of psychiatric conditions such as bipolar disorder [ 17 ], autism spectrum disorder [ 18 ] and cognition-related disorders [ 19 , 20 ]. More importantly, upregulated Npas4 expression has been reported in various brain insults, including focal and global ischemic stroke [ 4 , 21 , 22 , 23 , 24 ].…”

Expression of Npas4 after Cerebral Ischemia in A MCAO Rat Model

“…In addition, the up-regulated Npas4 protein expression was detected in both cortex and basal ganglia in rat brain exposed to ischemic insult, consistent with previous studies, which show that Npas4 expression in global cerebral ischemia. 16 Our research indicates Npas4 up-regulates in response to cerebral ischemia in acute phase. This early regulation suggests that Npas4 may be involved in the pathophysiological…”