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Degradation of the chondroitin sulfate proteoglycans of the extracellular matrix (ECM) by injections of the bacterial enzyme chondroitinase ABC (ChABC) in the basolateral amygdala (BLA) does not impair fear memory formation but accelerates its extinction and disrupts its reactivation. These observations suggest that the treatment might selectively interfere with the post-extinction features of neurons that mediate the reinstatement of fear. Here, we report that ChABC mice show regular fear memory and memory-driven c-fos activation and dendritic spine formation in the BLA. These mice then rapidly extinguish their fear response and exhibit a post-extinction concurrent reduction in c-fos activation and large dendritic spines that extends to the anterior cingulate cortex 7 days later. At this remote time point, fear renewal and fear retrieval are impaired. These findings show that a non-cellular component of the brain tissue controls post-extinction levels of neuronal activity and spine enlargement in the regions sequentially remodelled during the formation of recent and remote fear memory. By preventing BLA and aCC neurons to retain neuronal features that serve to reactivate an extinguished fear memory, ECM digestion might offer a therapeutic strategy for durable attenuation of traumatic memories.

Background: Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronal cells to prevent functional deficits and cognitive deterioration. Here, we exploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function in peritumoral areas., Methods: We performed a microarray transcriptomic and in-depth proteomic analysis to characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle- and CNF1-treated glioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas., Results: Administration of CNF1 triggered molecular and morphological hallmarks of senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivo induced glioma cell senescence and potently reduced tumor volumes. In peritumoral areas of glioma-bearing mice, neurons showed a shrunken dendritic arbor and severe functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improved several physiological properties of pyramidal neurons, demonstrating functional preservation of the cortical network., Conclusions: Our findings demonstrate that CNF1 reduces glioma volume while at the same time maintaining the physiological and structural properties of peritumoral neurons. These data indicate a promising strategy for the development of more effective antiglioma therapies., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice., (© 2014 Wiley Periodicals, Inc.)

The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons remains elusive. Using transgenic mice conditionally expressing a dominant-negative CREB (CREBS133A: mCREB) mutant, we found that inhibiting CREB function does not alter spine density, spine morphology, and levels of polymerized actin in naive CA1 neurons. CREB inhibition, however, impaired contextual fear conditioning and produced a learning-induced collapse of spines associated with a blockade of learning-dependent increase in actin polymerization. Blocking mCREB expression with doxycycline rescued memory and restored a normal pattern of learning-induced spines, demonstrating that CREB controls structural adaptations of neurons selectively involved in memory formation.

Although hippocampal-cortical interactions are crucial for the formation of enduring declarative memories, synaptic events that govern long-term memory storage remain mostly unclear. We present evidence that neuronal structural changes, i.e., dendritic spine growth, develop sequentially in the hippocampus and anterior cingulate cortex (aCC) during the formation of recent and remote contextual fear memory. We found that mice placed in a conditioning chamber for one 7 min conditioning session and exposed to five footshocks (duration, 2 s; intensity, 0.7 mA; interstimulus interval, 60 s) delivered through the grid floor exhibited robust fear response when returned to the experimental context 24 h or 36 d after the conditioning. We then observed that their fear response at the recent, but not the remote, time point was associated with an increase in spine density on hippocampal neurons, whereas an inverse temporal pattern of spine density changes occurred on aCC neurons. At each time point, hippocampal or aCC structural alterations were achieved even in the absence of recent or remote memory tests, thus suggesting that they were not driven by retrieval processes. Furthermore, ibotenic lesions of the hippocampus impaired remote memory and prevented dendritic spine growth on aCC neurons when they were performed immediately after the conditioning, whereas they were ineffective when performed 24 d later. These findings reveal that gradual structural changes modifying connectivity in hippocampal-cortical networks underlie the formation and expression of remote memory, and that the hippocampus plays a crucial but time-limited role in driving structural plasticity in the cortex.

Rationale: Reelin, a large extracellular matrix glycoprotein, is down-regulated in the brain of schizophrenic patients and of heterozygous reeler mice (rl/+). The behavioral phenotype of rl/- mice, however, matches only partially the schizophrenia hallmarks., Objectives: We recently reported (Marrone et al., Eur J Neurosci 24:20062-22070, 2006) that homozygous reeler mutants (rl/rl) exhibit reduced density of parvalbumin-positive (PV+) GABAergic interneurons in anatomically circumscribed regions of the neostriatum. Assuming that in rl/+ mice may also show regional reduction of striatal GABAergic interneurons, behavioral impairments should selectively emerge in tasks depending on specifically altered striatal circuits., Materials and Methods: We mapped the density of striatal PV+ interneurons in rl/+ and wild-type (+/+) mice and measured their performance in tasks depending on distinct striatal subregions., Results: Our findings show that, contrary to what would be expected on the basis of gene dosage criteria, the striatal regions in which rl/rl mice exhibited decreased density of PV+ interneurons were either unaltered (rostral striatum) or equally altered (dorsomedial and ventromedial intermediate striatum, caudal striatum) in rl/+ mice. The anatomical findings were paralleled by behavioral deficits in fear extinction and latent inhibition, respectively, requiring the dorsomedial and ventromedial striatal regions. Conversely, active avoidance performance, which requires the dorsolateral region, was unaffected., Conclusions: Reelin haploinsufficiency alters the density of PV+ neurons in circumscribed regions of the striatum and selectively disrupts behaviors sensitive to dysfunction of these targeted regions. This aspect should be considered when designing experiments aimed at evaluating the impact of reelin haploinsufficiency in schizophrenia-associated cognitive disturbances in rl/+ mutants.

Synaptic activity-dependent phosphorylation of the transcription factor cAMP response element binding protein (CREB) leads to CREB-dependent gene transcription, a process thought to underlie long-term hippocampal synaptic plasticity and memory formation. We previously reported that increasing CREB activity in glutamatergic neurons enhances synaptic plasticity and neuronal excitability. Whether these modifications are sufficient to promote hippocampal-dependent memory formation was not determined. Here, we provide direct evidence that a brief increase in CREB-dependent transcription in either CA1 or DG neurons, using in vivo viral vectors, is sufficient to boost memory for contextual representations, as tested in the contextual fear conditioning task, without affecting motor, pain, or anxiety behaviors.

Many neuronal disorders such as lissencephaly, epilepsy, and schizophrenia are caused by the abnormal migration of neurons in the developing brain. The role of the actin cytoskeleton in neuronal migration disorders has in large part remained elusive. Here we show that the F-actin depolymerizing factor n-cofilin controls cell migration and cell cycle progression in the cerebral cortex. Loss of n-cofilin impairs radial migration, resulting in the lack of intermediate cortical layers. Neuronal progenitors in the ventricular zone show increased cell cycle exit and exaggerated neuronal differentiation, leading to the depletion of the neuronal progenitor pool. These results demonstrate that mutations affecting regulators of the actin cytoskeleton contribute to the pathology of cortex development.

Changes in neuronal connectivity occurring upon the formation of aversive memory were examined in C57BL/6 (C57) mice 24 h after they were trained for tone fear conditioning (TFC) and contextual fear conditioning (CFC). Although TFC and CFC are amenable to distinct learning systems each involving a specific neural substrate, we found that mice trained in the two protocols showed the same increase in spine density and spine size in class I basolateral amygdala (BLA) and in dorsal hippocampus CA1 pyramidal neurons. Our findings suggest that, because of their remarkably functional hippocampus, C57 mice might engage this region in any fear situation they face. These observations raise a point relevant to aversive memory studies, i.e., how the peculiarity of memory in certain individuals impacts on the components of the fear circuitry. It is suggested that enhanced connectivity in brain regions dispensable for specific forms of learning could considerably increase the resistance of aversive memory traces to treatments aimed at disrupting them. [ABSTRACT FROM AUTHOR]

Consolidation of remote memory enhances immediate early genes induction (IEGs), augments the expression of the pre-synaptic growth associated protein-43 (GAP-43), and increases the density and size of dendritic spines in anterior cingulate (aCC) and infra-limbic (ILC) cortices. Remote memory extinction, however, does not uniformly alter consolidation-induced structural changes. In the aCC, the density, but not the size, of spines is reset to pseudo-conditioning levels while novel thin spines are formed in the ILC. Whether IEGs and GAP-43 also undergo region-specific changes upon remote memory extinction is undetermined. Here we confirm in the same batch of mice that c-Fos induction and GAP-43 expression are increased in both the aCC and the ILC 36 days after contextual fear conditioning. We then show that, in both regions, remote memory extinction is associated with decrease of c-Fos induction but no change in GAP-43 expression thus revealing similar, although protein-specific, pre-synaptic adaptations in aCC and ILC neurons. These observations, in addition to our previous report of region-specific post-synaptic structural changes, disclose a complex pattern of extinction-driven neocortical alterations suitable to support erasure or reinstatement of fear according to the environment demand. [ABSTRACT FROM AUTHOR]

Recently, the striatum has been implicated in the spread of epileptic seizures. As the absence of functional scaffolding protein Bassoon in mutant mice is associated with the development of pronounced spontaneous seizures, we utilized this new genetic model of epilepsy to investigate seizure-induced changes in striatal synaptic plasticity. Mutant mice showed reduced long-term potentiation in striatal spiny neurons, associated with an altered N-methyl-d-aspartate (NMDA) receptor subunit distribution, whereas GABAergic fast-spiking (FS) interneurons showed NMDA-dependent short-term potentiation that was absent in wild-type animals. Alterations in the dendritic morphology of spiny neurons and in the number of FS interneurons were also observed. Early antiepileptic treatment with valproic acid reduced epileptic attacks and mortality, rescuing physiological striatal synaptic plasticity and NMDA receptor subunit composition. However, morphological alterations were not affected by antiepileptic treatment. Our results indicate that, in Bsn mutant mice, initial morphological alterations seem to reflect a more direct effect of the abnormal genotype, whereas plasticity changes are likely to be caused by the occurrence of repeated cortical seizures. [ABSTRACT FROM AUTHOR]