[PMID: 21035445]

[PMID: 21035445]. disrupted ocular dominance plasticity [99]. Conversely, while transgenic overexpression of miRNA-132 in mice induced an increase in spine density, it impaired the ability of mice to perform in novel object recognition [95]. Altogether these data demonstrate the critical role of miRNA-132 expression in neuronal development and plasticity. As highlighted above, MiRNA-134 is a brain-specific microRNA which is expressed in neuronal dendrites. It was shown to negatively regulate the size of dendritic spines of rat hippocampal neurons by inhibiting the expression of Lim-domain-containing protein kinase 1 (LIMK1) which reorganizes the actin cytoskeleton dynamics Z-WEHD-FMK through phosphorylation and thereby inactivation of the actin depolymerizing factor cofilin [100]. Furthermore, it was shown that inhibition of miRNA-134 with antisense oligonucleotide restores CREB and BDNF levels, two proteins involved in synaptic plasticity, and rescues the impairment of long-term potentiation and plasticity observed in Z-WEHD-FMK a knockout mice model [37]. It was also shown that the brain-enriched miRNA-138, which is located in the dendritic compartment on rat hippocampal neurons, negatively regulates the size of dendritic spines. Indeed, miRNA-138 targets the expression of acyl protein thioesterase 1 (APT1), an enzyme known to depalmitoylate a number of substrates implicated in synaptic plasticity, including the G13 subunits of G proteins [101]. More specifically, miRNA-138 increases their membrane-bound state by reducing depalmitoylation of G13 subunits. This results in a prolonged activation of the downstream RhoA pathway and subsequent spine growth inhibition through the actin cytoskeleton reorganization. Along the same lines, recent studies have shown that miRNA-128 [102], another brain-enriched miRNA was implicated in the control of synaptic plasticity and memory. Its upregulation in the infralimbic prefrontal cortex is required to regulate plasticity in adult post-mitotic neurons and is involved in the formation of fear-extinction memory. This effect of miRNA128b on memory is mediated through negative regulation of the expression of plasticity-related genes such as the regulator of calmodulin signaling, Rcs and CREB1 [102]. More recently, it has been shown that its expression reduces dendritic growth and arborization of neurons, and changes their intrinsic excitability by targeting PHF6, a gene mutated in the cognitive disorder B?rjeson-Forssman-Lehmann syndrome [103]. Thanks to genetic approaches performed in Drosophila, other studies have provided direct evidence that miRNA pathways regulate learning and memory. A genetic screen identified four microRNAs, miRNA-9c, miRNA-31a, miRNA-974, mirNA-305 that reduced olfactory learning and memory formation and one microRNA, MiRNA-980 that, when inhibited, enhances memory formation [104]. More recently, it was shown that miR-980 overexpression impaired olfactory memory in Drosophila by targeting expression of the autism-susceptibility gene, A2bp1, a known RNA binding protein involved in alternative splicing [105]. Given the important role of miRNAs in the development and functions of the brain (Table ?11) as detailed here, it is not surprising that there is increasing evidence suggesting that the dysregulation or altered expression of these miRNAs may be associated to cognitive disorders. Some of these examples will be discussed in the following section. Table 1 Experimental validated miRNA-target interaction for miRNA involved in synaptic plasticity and function. targeting heat shock protein 70 in a human neuroblastoma cell line [120]. Given that the expression level of -synuclein is elevated in PD patients and that -synuclein expression may contribute to DA neuron degeneration, miRNA-based strategies may be an alternative exploitable therapeutic approach to modulate this abnormal upregulation Z-WEHD-FMK in PD. Besides -synuclein, the leucine-rich repeat kinase 2 (LRRK2), an enzyme involved in the early development Z-WEHD-FMK of neuronal processes [121], is another key protein involved in the etiology of PD. Mutations in LRKK2 are the most common genetic lesions associated with familial and sporadic PD cases [122]. Interestingly, it was shown that miRNA-205, which is highly expressed in wild Rabbit Polyclonal to NCAPG type mouse midbrain DN, directly inhibits the expression of LRRK2 protein..