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Summary: Proper polarization of newly generated neurons is a critical process for neural network formation and brain development. The pan-neurotrophin p75NTR receptor plays a key role in this process localizing asymmetrically in one of the differentiating neurites and specifying its axonal identity in response to neurotrophins. During axonal specification, p75NTR levels are transiently modulated, yet the molecular mechanisms underlying this process are not known. Here, we identified a previously uncharacterized natural antisense transcript, AS-p75, encoded within the p75NGFR mouse gene. Using an in vitro model of polarizing murine neurons, we found that AS-p75 and p75NTR display divergent expression profiles and that p75NTR expression levels increase upon competition or depletion of AS-p75, indicating that AS-p75 is a negative regulator of p75NTR expression. Depletion of AS-p75 also results in altered p75NTR subcellular distribution and affects the polarization process. Overall, our data uncovered AS-p75 as a modulator of p75NTR expression, offering new insights into the regulation of this neurotrophin receptor during in vitro neuronal polarization.

Epilepsy is a comorbidity associated with Alzheimer's disease (AD), often starting many years earlier than memory decline. Investigating this association in the early pre-symptomatic stages of AD can unveil new mechanisms of the pathology as well as guide the use of antiepileptic drugs to prevent or delay hyperexcitability-related pathological effects of AD. We investigated the impact of repeated seizures on hippocampal memory and amyloid-β (Aβ) load in pre-symptomatic Tg2576 mice, a transgenic model of AD. Seizure induction caused memory deficits and an increase in oligomeric Aβ42 and fibrillary species selectively in pre-symptomatic transgenic mice, and not in their wildtype littermates. Electrophysiological patch-clamp recordings in ex vivo CA1 pyramidal neurons and immunoblots were carried out to investigate the neuronal alterations associated with the behavioral outcomes of Tg2576 mice. CA1 pyramidal neurons exhibited increased intrinsic excitability and lower hyperpolarization-activated Ih current. CA1 also displayed lower expression of the hyperpolarization-activated cyclic nucleotide-gated HCN1 subunit, a protein already identified as downregulated in the AD human proteome. The antiepileptic drug lamotrigine restored electrophysiological alterations and prevented both memory deficits and the increase in extracellular Aβ induced by seizures. Thus our study provides evidence of pre-symptomatic hippocampal neuronal alterations leading to hyperexcitability and associated with both higher susceptibility to seizures and to AD-specific seizure-induced memory impairment. Our findings also provide a basis for the use of the antiepileptic drug lamotrigine as a way to counteract acceleration of AD induced by seizures in the early phases of the pathology.

Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.

Increasing evidence supports a model whereby memories are encoded by sparse ensembles of neurons called engrams, activated during memory encoding and reactivated upon recall. An engram consists of a network of cells that undergo long-lasting modifications of their transcriptional programs and connectivity. Ground-breaking advancements in this field have been made possible by the creative exploitation of the characteristic transcriptional responses of neurons to activity, allowing both engram labeling and manipulation. Nevertheless, numerous aspects of engram cell-type composition and function remain to be addressed. As recent transcriptomic studies have revealed, memory encoding induces persistent transcriptional and functional changes in a plethora of neuronal subtypes and non-neuronal cells, including glutamatergic excitatory neurons, GABAergic inhibitory neurons, and glia cells. Dissecting the contribution of these different cellular classes to memory engram formation and activity is quite a challenging yet essential endeavor. In this review, we focus on the role played by the GABAergic inhibitory component of the engram through two complementary lenses. On one hand, we report on available physiological evidence addressing the involvement of inhibitory neurons to different stages of memory formation, consolidation, storage and recall. On the other, we capitalize on a growing number of transcriptomic studies that profile the transcriptional response of inhibitory neurons to activity, revealing important clues on their potential involvement in learning and memory processes. The picture that emerges suggests that inhibitory neurons are an essential component of the engram, likely involved in engram allocation, in tuning engram excitation and in storing the memory trace.

In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis.

Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3′ UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3′ UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3′ UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity.