miRNA-132: a dynamic regulator of cognitive capacity

Abstract

Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5-fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal-dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation.

MicroRNAs and synaptic plasticity—a mutual relationship

“…Mir-132 levels in the hippocampal formation are also increased by other behavioural tasks, such as the Barnes maze or novel object recognition [62], suggesting an involvement of miR-132 in spatial memory formation. However, mice expressing miR-132 above the physiologically relevant level unexpectedly performed worse in the novel object recognition task [54,62] and the Barnes maze [62]. Excessive spine growth might be one of the side-effects of transgenic miR-132 overexpression that might limit the functional working range of neurons [62].…”

“…B 369: 20130515 acquisition, because virus-mediated inhibition in vivo leads to an impairment in the storage of temporally associated information [61]. Mir-132 levels in the hippocampal formation are also increased by other behavioural tasks, such as the Barnes maze or novel object recognition [62], suggesting an involvement of miR-132 in spatial memory formation. However, mice expressing miR-132 above the physiologically relevant level unexpectedly performed worse in the novel object recognition task [54,62] and the Barnes maze [62].…”

“…However, mice expressing miR-132 above the physiologically relevant level unexpectedly performed worse in the novel object recognition task [54,62] and the Barnes maze [62]. Excessive spine growth might be one of the side-effects of transgenic miR-132 overexpression that might limit the functional working range of neurons [62]. Similarly, viral overexpression of miR-132 in the perirhinal cortex abolished novel object recognition memory when tested 20 min, but not 24 h after the training session [63].…”

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

“…3A). In addition, to gain an even greater level of insight into the roles of these miRNAs in sculpting the gene expression in the hippocampus, we also performed high-throughput RNA-seq in mice that transgenically overexpress either miR-132 (Descried in Hansen et al 2010Hansen et al , 2013 or a newly generated miR-212 transgenic mouse line (Figs. 3B, 4).…”

“…To date, a number of studies have shown that both miRNAs are associated with impaired cognition when their expression levels are not maintained within a tightly regulated range (Scott et al 2012;Wang et al 2013;Kempf et al 2014). Moreover, while moderate overexpression (approximately fivefold increase) of miR-132 impairs learning and memory, small increases ( 1.5-fold) serve to facilitate performance on memoryassociated behavior tasks (Hansen et al 2013). This suggests that there exists an optimized level of miR-132 expression that can facilitate cognition, but that deviation from this range impairs neuronal function (Mellios et al 2011;Tognini et al 2011;Tognini and Pizzorusso 2012;Hansen et al 2013).…”