Pre-treatment with microRNA-181a Antagomir Prevents Loss of Parvalbumin Expression and Preserves Novel Object Recognition Following Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) can result in permanent impairment in memory and learning and may be a precursor to other neurological sequelae. Clinical treatments to ameliorate the effects of mTBI are lacking. Inhibition of microRNA-181a (miR-181a) is protective in several models of cerebral injury, but its role in mTBI has not been investigated. In the present study, miR-181a-5p antagomir was injected intracerebroventricularly 24 h prior to closed-skull cortical impact in young adult male mice. Paw withdrawal, open field, zero maze, Y maze, object location and novel object recognition tests were performed to assess neurocognitive dysfunction. Brains were assessed immunohistologically for the neuronal marker NeuN, the perineuronal net marker wisteria floribunda lectin (WFA), cFos, and the interneuron marker parvalbumin. Protein quantification was performed with immunoblots for synaptophysin and postsynaptic density 95 (PSD95). Fluorescent in situ hybridization was utilized to localize hippocampal miR-181a expression. MiR-181a antagomir treatment reduced neuronal miR-181a expression after mTBI, restored deficits in novel object recognition and increased hippocampal parvalbumin expression in the dentate gyrus. These changes were associated with decreased dentate gyrus hyperactivity indicated by a relative reduction in PSD95 and cFos expression. These results suggest that miR-181a inhibition may be a therapeutic approach to reduce hippocampal excitotoxicity and prevent cognitive dysfunction following mTBI.

Sex differences in cued fear responses and parvalbumin cell density in the hippocampus following repetitive concussive brain injuries in C57BL/6J mice

“…Parvalbumin-immunoreactive (PV-IR) interneurons comprise a large proportion of inhibitory GABAergic interneurons in the hippocampus (and amygdala), and are intricately involved in the neuronal circuitry required for FC acquisition, storage and retrieval [44–47]. Loss of PV-IR cells in the dentate gyrus, as observed here, has been reported previously in male rodents following LFP [48, 49] or concussive brain injury [50]. The loss of these inhibitory interneurons has been associated with increased dentate gyrus excitability [48] and a chronic, progressive loss of synaptic inhibition [49].…”

Curcumin Reduces Neuroinflammation and Improves the Impairments of Anesthetics on Learning and Memory by Regulating the Expression of miR-181a-5p

“…Various results indicate that miR-181a-5p plays an important role in ISO-induced cognitive impairment. Some research suggested that overexpression of miR-181a has been shown to contribute to brain nerve damage, including Parkinson’s disease and epilepsy [26, 27], and has been associated with behavioral changes following nerve damage in rodents [28]. Therefore, we hypothesized that overexpression of miR-181a-5p promoted the occurrence and progression of cognitive impairment and neuroinflammation in ISO-exposed rats.…”

“…Therefore, we hypothesized that overexpression of miR-181a-5p promoted the occurrence and progression of cognitive impairment and neuroinflammation in ISO-exposed rats. Mild traumatic brain injury can cause permanent damage to learning and memory ability, and Griffiths et al [28] found that inhibition of miR-181a expression could have a protective effect on brain injury in mice after injecting miR-181a inhibitor into mice with mild brain injury. This study also supports our conclusions.…”

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…Also of particular interest was no change in PV-expressing cell density in the AMY and the HP, as PV-IR cells in these regions have been demonstrated to be important for memory consolidation. 54,56 PV-IR cell density in the dentate gyrus of the HP has been previously reported to decrease following experimental TBI, 39,58,61,62 and this cell loss has been associated with impaired performance on contextual and cued DFC test performance following repetitive concussive brain injuries in male mice. 39 But, another pathological mechanism must account for impaired TFC performance following repeated CHIMERA injuries, as well as for the observed MWM deficits.…”

“…Main effect of injury, CHIMERA < Sham Main effect of sex, Male < Female TFC-cue test, total freezing during trace periods (Fig. 9D) COGNITIVE DYSFUNCTION FOLLOWING CHIMERA focal concussive 39,58 or lateral fluid percussion injury, [59][60][61][62] which results in a mixed focal-diffuse injury. In addition, CCI resulted in a reduction in PV-expressing interneurons in both the HP and AMY.…”