Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.

BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5-/y rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Selective estrogen receptor activation prior to global cerebral ischemia in female rats impacts microglial activation and anxiety-like behaviors without effects on CA1 neuronal injury.

Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100 µg/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERß agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.

Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice.

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

Protocol for calcium imaging and analysis of hippocampal CA1 activity evoked by non-spatial stimuli.

The hippocampus has a major role in processing spatial information but has been found to encode non-spatial information from multisensory modalities in recent studies. Here, we present a protocol for recording non-spatial stimuli (visual, auditory, and a combination) that evoked calcium activity of hippocampal CA1 neuronal ensembles in C57BL/6 mice using a miniaturized fluorescence microscope. We describe steps for experimental apparatus setup, surgical procedures, software development, and neuronal population activity analysis. For complete details on the use and execution of this protocol, please refer to Sun et al.1.

Urolithin A Inhibits Anterior Basolateral Amygdala to Ventral Hippocampal CA1 Circuit to Ameliorate Amyloid-ß-Impaired Social Ability.

Background: Anxiety and social withdrawal are highly prevalent among patients with Alzheimer's disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective: This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods: We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results: In 5xFAD mice, we observed significant amyloid-ß (Aß) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aß accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions: The aBLA-vCA1 circuit is a vulnerable pathway in response to Aß accumulation during the progression of AD and plays a crucial role in Aß-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aß-impaired social ability.

Repeated diagnostic ultrasound exposure modifies the structural properties of CA1 dendrites and alters the hippocampal transcriptome.

The development of neurons is regulated by several spatiotemporally changing factors, which are crucial to give the ability of neurons to form functional networks. While external physical stimuli may impact the early developmental stages of neurons, the medium and long-term consequences of these influences have yet to be thoroughly examined. Using an animal model, this study focuses on the morphological and transcriptome changes of the hippocampus that may occur as a consequence of fetal ultrasound examination. We selectively labeled CA1 neurons of the hippocampus with in-utero electroporation to analyze their morphological features. Furthermore, certain samples also went through RNA sequencing after repetitive ultrasound exposure. US exposure significantly changed several morphological properties of the basal dendritic tree. A notable increase was also observed in the density of spines on the basal dendrites, accompanied by various alterations in individual spine morphology. Transcriptome analysis revealed several up or downregulated genes, which may explain the molecular background of these alterations. Our results suggest that US-derived changes in the dendritic trees of CA1 pyramidal cells might be connected to modification of the transcriptome of the hippocampus and may lead to an increased dendritic input.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

Differential disruptions in population coding along the dorsal-ventral axis of CA1 in the APP/PS1 mouse model of Aß pathology.

Alzheimer's Disease (AD) is characterized by a range of behavioral alterations, including memory loss and psychiatric symptoms. While there is evidence that molecular pathologies, such as amyloid beta (Aß), contribute to AD, it remains unclear how this histopathology gives rise to such disparate behavioral deficits. One hypothesis is that Aß exerts differential effects on neuronal circuits across brain regions, depending on the neurophysiology and connectivity of different areas. To test this, we recorded from large neuronal populations in dorsal CA1 (dCA1) and ventral CA1 (vCA1), two hippocampal areas known to be structurally and functionally diverse, in the APP/PS1 mouse model of amyloidosis. Despite similar levels of Aß pathology, dCA1 and vCA1 showed distinct disruptions in neuronal population activity as animals navigated a virtual reality environment. In dCA1, pairwise correlations and entropy, a measure of the diversity of activity patterns, were decreased in APP/PS1 mice relative to age-matched C57BL/6 controls. However, in vCA1, APP/PS1 mice had increased pair-wise correlations and entropy as compared to age matched controls. Finally, using maximum entropy models, we connected the microscopic features of population activity (correlations) to the macroscopic features of the population code (entropy). We found that the models' performance increased in predicting dCA1 activity, but decreased in predicting vCA1 activity, in APP/PS1 mice relative to the controls. Taken together, we found that Aß exerts distinct effects across different hippocampal regions, suggesting that the various behavioral deficits of AD may reflect underlying heterogeneities in neuronal circuits and the different disruptions that Aß pathology causes in those circuits.

Neuroprotection of macamide in a mouse model of Alzheimer's disease involves Nrf2 signaling pathway and gut microbiota.

The underlying mechanisms of macamide's neuroprotective effects in Alzheimer's disease (AD) were investigated in the paper. Macamides are considered as unique ingredients in maca. Improvement effects and mechanisms of macamide on cognitive impairment have not been revealed. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to acetylcholinesterase (AChE). N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) was selected to study the following experiments because it can stably bind to AChE with a strong binding energy. The animal experiments showed that M 18:2 prevented the scopolamine (SCP)-induced cognitive impairment and neurotransmitter disorders, increased the positive rates of Nrf2 and HO-1 in hippocampal CA1, improved the synaptic plasticity by maintaining synaptic morphology and increasing the synapse density. Moreover, the contents of IL-1ß, IL-6, and TNF-α in the hippocampus, serum, and colon were reduced by M 18:2. Furthermore, M 18:2 promoted colonic epithelial integrity and partially restored the composition of the gut microbiota to normal, including decreased genera Clostridiales_unclassified and Lachnospiraceae_unclassified, as well as increased genera Muribaculaceae_unclassified, Muribaculum, Alistipes, and Bacteroides, which may be the possible biomarkers of cognitive aging. In summary, M 18:2 exerted neuroprotective effects on SCP-induced AD mice possibly via activating the Nrf2/HO-1 signaling pathway and modulating the gut microbiota.

Pregnancy-induced oxidative stress and inflammation are not associated with impaired maternal neuronal activity or memory function.

Pregnancy is associated with neural and behavioral plasticity, systemic inflammation, and oxidative stress, yet the impact of inflammation and oxidative stress on maternal neural and behavioral plasticity during pregnancy is unclear. We hypothesized that healthy pregnancy transiently reduces learning and memory and these deficits are associated with pregnancy-induced elevations in inflammation and oxidative stress. Cognitive performance was tested with novel object recognition (recollective memory), Morris water maze (spatial memory), and open field (anxiety-like) behavior tasks in female Sprague-Dawley rats of varying reproductive states [nonpregnant (nulliparous), pregnant (near term), and 1-2 mo after pregnancy (primiparous); n = 7 or 8/group]. Plasma and CA1 proinflammatory cytokines were measured with a MILLIPLEX magnetic bead assay. Plasma oxidative stress was measured via advanced oxidation protein products (AOPP) assay. CA1 markers of oxidative stress, neuronal activity, and apoptosis were quantified via Western blot analysis. Our results demonstrate that CA1 oxidative stress-associated markers were elevated in pregnant compared with nulliparous rats (P ≤ 0.017) but there were equivalent levels in pregnant and primiparous rats. In contrast, reproductive state did not impact CA1 inflammatory cytokines, neuronal activity, or apoptosis. Likewise, there was no effect of reproductive state on recollective or spatial memory. Even so, spatial learning was impaired (P ≤ 0.007) whereas anxiety-like behavior (P ≤ 0.034) was reduced in primiparous rats. Overall, our data suggest that maternal hippocampal CA1 is protected from systemic inflammation but vulnerable to peripartum oxidative stress. Peripartum oxidative stress elevations, such as in pregnancy complications, may contribute to peripartum neural and behavioral plasticity.NEW & NOTEWORTHY Healthy pregnancy is associated with elevated maternal systemic and brain oxidative stress. During postpregnancy, brain oxidative stress remains elevated whereas systemic oxidative stress is resolved. This sustained maternal brain oxidative stress is associated with learning impairments and decreased anxiety-like behavior during the postpregnancy period.

Tuning synaptic strength by regulation of AMPA glutamate receptor localization.

Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA-type glutamate receptors (AMPARs). A combination of AMPAR structural data, super-resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever-clearer picture of how AMPARs are recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse.

Cadmium inhibits calcium activity in hippocampal CA1 neurons of freely moving mice.

Cadmium (Cd) is a ubiquitous toxic heavy metal and a potential neurotoxicant due to its wide use in industrial manufacturing processes and commercial products, including fertilizers. The general population is exposed to Cd through food and smoking due to high transfer rates of Cd from contaminated soil. Cd has been shown to mimic calcium ions (Ca2+) and interfere with intracellular Ca2+ levels and Ca2+ signaling in in vitro studies. However, nothing is known about Cd's effects on Ca2+ activity in neurons in live animals. This study aimed to determine if Cd disrupts Ca2+ transients of neurons in CA1 region of the hippocampus during an associative learning paradigm. We utilized in vivo Ca2+ imaging in awake, freely moving C57BL/6 mice to measure Ca2+ activity in CA1 excitatory neurons expressing genetically encoded Ca2+ sensor GCaMP6 during an associative learning paradigm. We found that a smaller proportion of neurons are activated in Cd-treated groups compared with control during fear conditioning, suggesting that Cd may contribute to learning and memory deficit by reducing the activity of neurons. We observed these effects at Cd exposure levels that result in blood Cd levels comparable with the general U.S. population levels. This provides a possible molecular mechanism for Cd interference of learning and memory at exposure levels relevant to U.S. adults. To our knowledge, our study is the first to describe Cd effects on brain Ca2+ activity in vivo in freely behaving mice. This study provides evidence for impairment of neuronal calcium activity in hippocampal CA1 excitatory neurons in freely moving mice following cadmium exposure.

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors.

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition.

AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Mouse hippocampal CA1 VIP interneurons detect novelty in the environment and support recognition memory.

In the CA1 hippocampus, vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) play a prominent role in disinhibitory circuit motifs. However, the specific behavioral conditions that lead to circuit disinhibition remain uncertain. To investigate the behavioral relevance of VIP-IN activity, we employed wireless technologies allowing us to monitor and manipulate their function in freely behaving mice. Our findings reveal that, during spatial exploration in new environments, VIP-INs in the CA1 hippocampal region become highly active, facilitating the rapid encoding of novel spatial information. Remarkably, both VIP-INs and pyramidal neurons (PNs) exhibit increased activity when encountering novel changes in the environment, including context- and object-related alterations. Concurrently, somatostatin- and parvalbumin-expressing inhibitory populations show an inverse relationship with VIP-IN and PN activity, revealing circuit disinhibition that occurs on a timescale of seconds. Thus, VIP-IN-mediated disinhibition may constitute a crucial element in the rapid encoding of novelty and the acquisition of recognition memory.

Preventive effect of propolis on cognitive decline in Alzheimer's disease model mice.

Brazilian green propolis (propolis) is a chemically complex resinous substance that is a potentially viable therapeutic agent for Alzheimer's disease. Herein, propolis induced a transient increase in intracellular Ca2+ concentration ([Ca2+]i) in Neuro-2A cells; moreover, propolis-induced [Ca2+]i elevations were suppressed prior to 24-h pretreatment with amyloid-ß. To reveal the effect of [Ca2+]i elevation on impaired cognition, we performed memory-related behavioral tasks in APP-KI mice relative to WT mice at 4 and 12 months of age. Propolis, at 300-1000 mg/kg/d for 8 wk, significantly ameliorated cognitive deficits in APP-KI mice at 4 months, but not at 12 months of age. Consistent with behavioral observations, injured hippocampal long-term potentiation was markedly ameliorated in APP-KI mice at 4 months of age following repeated propolis administration. In addition, repeated administration of propolis significantly activated intracellular calcium signaling pathway in the CA1 region of APP-KI mice. These results suggest a preventive effect of propolis on cognitive decline through the activation of intracellular calcium signaling pathways in CA1 region of AD mice model.

Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

Inhibition of 14-3-3 proteins increases the intrinsic excitability of mouse hippocampal CA1 pyramidal neurons.

14-3-3 proteins are a family of regulatory proteins that are abundantly expressed in the brain and enriched at the synapse. Dysfunctions of these proteins have been linked to neurodevelopmental and neuropsychiatric disorders. Our group has previously shown that functional inhibition of these proteins by a peptide inhibitor, difopein, in the mouse brain causes behavioural alterations and synaptic plasticity impairment in the hippocampus. Recently, we found an increased cFOS expression in difopein-expressing dorsal CA1 pyramidal neurons, indicating enhanced neuronal activity by 14-3-3 inhibition in these cells. In this study, we used slice electrophysiology to determine the effects of 14-3-3 inhibition on the intrinsic excitability of CA1 pyramidal neurons from a transgenic 14-3-3 functional knockout (FKO) mouse line. Our data demonstrate an increase in intrinsic excitability associated with 14-3-3 inhibition, as well as reveal action potential firing pattern shifts after novelty-induced hyperlocomotion in the 14-3-3 FKO mice. These results provide novel information on the role 14-3-3 proteins play in regulating intrinsic and activity-dependent neuronal excitability in the hippocampus.

Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning.

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

Focal clusters of peri-synaptic matrix contribute to activity-dependent plasticity and memory in mice.

Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we hypothesize that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to these processes. We show that clusters of the peri-synaptic ECM, recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. Using CS56 co-immunoprecipitation of synaptosomal proteins, we identify several molecules involved in Ca2+ signaling, vesicle cycling, and AMPA-receptor exocytosis, thus suggesting a role in long-term potentiation (LTP). Finally, we show that, in the CA1 hippocampal region, the attenuation of CS56 glycoepitopes, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in mice. These findings show that activity-dependent remodeling of the peri-synaptic ECM regulates the induction and consolidation of LTP, contributing to hippocampal-dependent memory.