Excitatory Synaptic Transmission In Hippocampus Research Articles

Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology.

N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B subunit incorporation to a later predominance of GluN2A. This GluN2B to GluN2A shift alters NMDAR calcium conductance dynamics and intracellular molecular signaling that are individually regulated by distinct GluN2 signaling domains and temporally align with developmental alterations in dendritic and synaptic plasticity. However, the impacts of individual GluN2B to GluN2A signaling domains on neuronal development remain unknown. Ionotropic and intracellular signaling domains of GluN2 subunits were separated by creating chimeric GluN2 subunits that were expressed in two transgenic mouse lines. Western blot and immunoprecipitation revealed that roughly one third of native synaptic NMDARs were replaced by transformed NMDARs without altering total synaptic NMDAR content. Schaffer collateral synaptic strength was transiently increased in acutely prepared hippocampal slices at just over 3 weeks of age in animals overexpressing the GluN2B carboxy terminus. Long-term potentiation (LTP) induction following lower frequency stimulation was regulated by GluN2 ionotropic signaling domains in an age-dependent manner and LTP maintenance was enhanced by overexpression of the GluN2B CTD in mature animals. After higher frequency stimulation, the induction and maintenance of LTP were increased in young adult animals overexpressing the GluN2B ionotropic signaling domains but reduced in juveniles just over 3 weeks of age. Confocal imaging of green fluorescent protein (GFP)- labeled CA1 pyramidal neurons revealed no alterations in dendritic morphology or spine density in mice expressing chimeric GluN2 subunits. These results illustrate how individual GluN2 subunit signaling domains do or do not control physiological and morphological development of hippocampal excitatory neurons and better clarify the neurobiological factors that govern hippocampal maturation. SIGNIFICANCE STATEMENT: A developmental reduction in the magnitude of hippocampal long-term synaptic potentiation (LTP) and a concomitant improvement in spatial maze performance coincide with greater incorporation of GluN2A subunits into synaptic NMDARs. Corroborating our prior discovery that overexpression of GluN2A-type ionotropic signaling domains enables context-based navigation in immature mice, GluN2A-type ionotropic signaling domain overexpression reduces LTP induction threshold and magnitude in immature mice. Also, we previously found that GluN2B carboxy terminal domain (CTD) overexpression enhances long-term spatial memory in mature mice and now report that the GluN2B CTD is associated with greater amplitude of LTP after induction in mature mice. Thus, the late postnatal maturation of context encoding likely relies on a shift toward GluN2A-type ionotropic signaling and a reduction in the threshold to induce LTP while memory consolidation and LTP maintenance are regulated by GluN2B subunit CTD signaling.

Selective inhibition of cannabinoid CB1 receptor-evoked signalling by the interacting protein GAP43

Cannabinoids exert pleiotropic effects on the brain by engaging the cannabinoid CB1 receptor (CB1R), a presynaptic metabotropic receptor that regulates key neuronal functions in a highly context-dependent manner. We have previously shown that CB1R interacts with growth-associated protein of 43 kDa (GAP43) and that this interaction inhibits CB1R function on hippocampal excitatory synaptic transmission, thereby impairing the therapeutic effect of cannabinoids on epileptic seizures in vivo. However, the underlying molecular features of this interaction remain unexplored. Here, we conducted mechanistic experiments on HEK293T cells co-expressing CB1R and GAP43 and show that GAP43 modulates CB1R signalling in a strikingly selective manner. Specifically, GAP43 did not affect the archetypical agonist-evoked (i) CB1R/Gi/o protein-coupled signalling pathways, such as cAMP/PKA and ERK, or (ii) CB1R internalization and intracellular trafficking. In contrast, GAP43 blocked an alternative agonist-evoked CB1R-mediated activation of the cytoskeleton-associated ROCK signalling pathway, which relied on the GAP43-mediated impairment of CB1R/Gq/11 protein coupling. GAP43 also abrogated CB1R-mediated ROCK activation in mouse hippocampal neurons, and this process led in turn to a blockade of cannabinoid-evoked neurite collapse. An NMR-based characterization of the CB1R-GAP43 interaction supported that GAP43 binds directly and specifically through multiple amino acid stretches to the C-terminal domain of the receptor. Taken together, our findings unveil a CB1R-Gq/11-ROCK signalling axis that is selectively impaired by GAP43 and may ultimately control neurite outgrowth.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects.

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

A centronuclear myopathy-causing mutation in dynamin-2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease.

Dynamin-2 (DNM2) is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in DNM2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a DNM2 CNM-causing mutation influences the CNS function. Heterozygous mice harbouring the p.R465W mutation in Dnm2 (HTZ), the most common causing autosomal dominant CNM, were used as the disease model. We evaluated dendritic arborization and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. HTZ hippocampal neurons exhibited reduced dendritic arborization and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the Dnm2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. Our findings suggest that the Dnm2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that Dnm2 plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.

Neonatal ketamine exposure impairs infrapyramidal bundle pruning and causes lasting increase in excitatory synaptic transmission in hippocampal CA3 neurons

Preclinical models demonstrate that nearly all anesthetics cause widespread neuroapoptosis in the developing brains of infant rodents and non-human primates. Anesthesia-induced developmental apoptosis is succeeded by prolonged neuropathology in the surviving neurons and lasting cognitive impairments, suggesting that anesthetics interfere with the normal developmental trajectory of the brain. However, little is known about effects of anesthetics on stereotyped axonal pruning, an important developmental algorithm that sculpts neural circuits for proper function. Here, we proposed that neonatal ketamine exposure may interfere with stereotyped axonal pruning of the infrapyramidal bundle (IPB) of the hippocampal mossy fiber system and that impaired pruning may be associated with alterations in the synaptic transmission of CA3 neurons. To test this hypothesis, we injected postnatal day 7 (PND7) mouse pups with ketamine or vehicle over 6 h and then studied them at different developmental stages corresponding to IPB pruning (PND20–40). Immunohistochemistry with synaptoporin (a marker of mossy fibers) revealed that in juvenile mice treated with ketamine at PND7, but not in vehicle-treated controls, positive IPB fibers extended farther into the stratum pyramidale of CA3 region. Furthermore, immunofluorescent double labeling for synaptoporin and PSD-95 strongly suggested that the unpruned IPB caused by neonatal ketamine exposure makes functional synapses. Importantly, patch-clamp electrophysiology for miniature excitatory postsynaptic currents (mEPSCs) in acute brain slices ex vivo revealed increased frequency and amplitudes of mEPSCs in hippocampal CA3 neurons in ketamine-treated groups when compared to vehicle controls. We conclude that neonatal ketamine exposure interferes with normal neural circuit development and that this interference leads to lasting increase in excitatory synaptic transmission in hippocampus.

Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms

Antiseizure medication is the mainstay of treatment for seizures, and adjunctive therapy is widely used to achieve adequate seizure control in patients with epilepsy who fail to respond to the first monotherapy. The newly developed antiepileptic drug cenobamate (YKP3089) as an adjunctive therapy improved seizure control in patients with uncontrolled focal seizures. Cenobamate is thought to reduce neuronal excitability through action on multiple targets, including GABA A receptors (GABAARs) and voltage-gated sodium channels. However, its effects on brain function and synaptic plasticity are unclear. Here, we explored the behavioral, synaptic, and cellular actions of cenobamate. Cenobamate influenced novel object recognition, object location memory, and Morris water maze performance in mice. Cenobamate enhanced inhibitory postsynaptic potentials by prolonging inhibitory postsynaptic current (IPSC) decay without affecting presynaptic GABA release or the peak amplitude of IPSCs. In addition, cenobamate suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation. A reduction in neuronal excitability induced by cenobamate was associated with an elevation of action potential (AP) threshold, and which progressively increased in later APs during repetitive firing, indicating the activity-dependent modulation of neuronal sodium currents. Cenobamate suppressed neuronal excitability under the condition that GABAergic neurotransmission is excitatory, and administration of cenobamate rapidly enhanced the phosphorylation of eukaryotic elongation factor 2 in the hippocampus of adult and neonatal mice. Collectively, these results suggest that the combined action of cenobamate on sodium currents and GABAAR-mediated synapse responses results in reduced excitability in neurons.

Impaired learning and memory generated by hyperthyroidism is rescued by restoration of AMPA and NMDA receptors function

Hyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.

Hippocampal Excitatory Synaptic Transmission and Plasticity Are Differentially Altered during Postnatal Development by Loss of the X-Linked Intellectual Disability Protein Oligophrenin-1.

Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling. Ophn1 knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology. We also previously reported a reduction in dendritic spine density in the adult hippocampus of KO mice. Yet the nature of the deficits occurring in these mice during postnatal development remains elusive. Here, we show that juvenile KO mice present normal basal synaptic transmission, but altered synaptic plasticity, with a selective impairment in long-term depression, but no change in long-term potentiation. This contrasts with the functional deficits that these mice display at the adult stage, as we found that both basal synaptic transmission and long-term potentiation are reduced at later stages, due to presynaptic alterations. In addition, the number of excitatory synapses in adult is increased, suggesting some unsuccessful compensation. Altogether, these results suggest that OPHN1 function at synapses is differentially affected during maturation of the brain, which provides some therapeutic opportunities for early intervention.

Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.

Patients with monoallelic bromodomain and PHD finger-containing protein 1 (BRPF1) mutations showed intellectual disability. The hippocampus has essential roles in learning and memory. Our previous work indicated that Brpf1 was specifically and strongly expressed in the hippocampus from the perinatal period to adulthood. We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, and mRNA-Seq on shBrpf1-infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics, and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knock down Brpf1 in vivo and examined the learning and memory ability by Morris water maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that Brpf1 mild knockdown in the hippocampus showed a decreasing trend on the spatial learning and memory ability of mice. Finally, mRNA-Seq analyses showed that genes related to learning, memory, and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, and Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory synaptic transmission and reduced spatial learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.

Maternal Immune Activation Affects Hippocampal Excitatory and Inhibitory Synaptic Transmission in Offspring From an Early Developmental Period to Adulthood.

One of the risk factors for schizophrenia is maternal infection. We have previously shown that Polyriboinosinic-polyribocytidylic acid (poly I:C) induced maternal immune activation in mice caused histological changes in the hippocampal CA1 area of offspring during the developmental period and impaired sensorimotor gating in offspring during adulthood, resulting in behavioral changes. However, it remains unclear how maternal immune activation functionally impacts the hippocampal neuronal activity of offspring. We studied the effect of prenatal poly I:C treatment on synaptic transmission of hippocampal CA1 pyramidal cells in postnatal and adult offspring. Treatment with poly I:C diminished excitatory and enhanced inhibitory (GABAergic) synaptic transmission on pyramidal cells in adult offspring. During the early developmental period, we still observed that treatment with poly I:C decreased excitatory synaptic transmission and potentially increased GABAergic synaptic transmission, which was uncovered under a condition of high extracellular potassium-activated neurons. In conclusion, we demonstrate that maternal immune activation decreased excitatory and increased inhibitory synaptic transmission on hippocampal pyramidal cells from an early developmental period to adulthood, which could result in net inhibition in conjunction with poor functional organization and integration of hippocampal circuits.

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.

Melanopsin for precise optogenetic activation of astrocyte-neuron networks.

Optogenetics has been widely expanded to enhance or suppress neuronal activity and it has been recently applied to glial cells. Here, we have used a new approach based on selective expression of melanopsin, a G-protein-coupled photopigment, in astrocytes to trigger Ca2+ signaling. Using the genetically encoded Ca2+ indicator GCaMP6f and two-photon imaging, we show that melanopsin is both competent to stimulate robust IP3-dependent Ca2+ signals in astrocyte fine processes, and to evoke an ATP/Adenosine-dependent transient boost of hippocampal excitatory synaptic transmission. Additionally, under low-frequency light stimulation conditions, melanopsin-transfected astrocytes can trigger long-term synaptic changes. In vivo, melanopsin-astrocyte activation enhances episodic-like memory, suggesting melanopsin as an optical tool that could recapitulate the wide range of regulatory actions of astrocytes on neuronal networks in behaving animals. These results describe a novel approach using melanopsin as a precise trigger for astrocytes that mimics their endogenous G-protein signaling pathways, and present melanopsin as a valuable optical tool for neuron-glia studies.

Inhibition of iNOS ameliorates traumatic stress-induced deficits in synaptic plasticity and memory

Post-traumatic stress disorder (PTSD) is characterized by cognitive deficits including impaired explicit memory. Nitric oxide (NO), which is generated by nitric oxide synthase (NOS), has been considered to modulate learning and memory. In current study, we evaluated the role of NOS in the mouse model of PTSD. We established the immobilization (IMO) mouse model of PTSD and analyzed mice behavior, NOS expression and hippocampal excitatory synaptic transmission after immobilization. We inhibited iNOS by applying of iNOS inhibitor 1400 W and monitored the effect of iNOS inhibition by 1400 W in IMO mice. IMO induced iNOS expression and resulted in abnormal behavior and deficits in synaptic plasticity and memory in mice. Inhibition of iNOS rescued abnormal hippocampal long-term potentiation and abnormal behavior in IMO mice. Inhibition of iNOS ameliorates traumatic stress-induced deficits in synaptic plasticity and memory.

Evaluation of β‐Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission

β-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration-response curve shows that the efficacy of LINS04008 is highest in the series (EC50 = 91.32 µM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps.

Role of Hippocampal Neuronal Excitatory Synaptic Transmission Changes in Modulating Neurocognitive Impairments in a Mouse Model of Chronic Intermittent Hypoxia

Role of Hippocampal Neuronal Excitatory Synaptic Transmission Changes in Modulating Neurocognitive Impairments in a Mouse Model of Chronic Intermittent Hypoxia

The neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson’s disease-like symptoms following administration to mice, monkeys, and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP+) to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra (SN). Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, SN and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP+. Here, we present data showing that acute bath-application of MPP+ elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP+ were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters did not prevent but increased the depression of excitatory post-synaptic field potentials. In the search for a possible mechanism, we observed that MPP+ reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory post-synaptic currents. The acute effect of MPP+ on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP+ affects hippocampal synaptic transmission by enhancing some aspects of the hippocampal GABAergic system.

Multiple forms of metaplasticity at a single hippocampal synapse during late postnatal development

Metaplasticity refers to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Numerous forms of developmental metaplasticity are observed at Schaffer collateral synapses in the rat hippocampus at the end of the third postnatal week. Emergence of spatial learning and memory at this developmental stage suggests possible involvement of metaplasticity in the final maturation of the hippocampus. Three distinct metaplastic phenomena are apparent. (1) As transmitter release probability increases with increasing age, presynaptic potentiation is reduced. (2) Alterations in the composition and channel conductance properties of AMPARs facilitate the induction of postsynaptic potentiation with increasing age. (3) Low frequency stimulation inhibits subsequent induction of potentiation in animals older but not younger than 3 weeks of age. Thus, many forms of plasticity expressed at SC-CA1 synapses are different in rats younger and older than 3 weeks of age, illustrating the complex orchestration of physiological modifications that underlie the maturation of hippocampal excitatory synaptic transmission. This review paper describes three late postnatal modifications to synaptic plasticity induction in the hippocampus and attempts to relate these metaplastic changes to developmental alterations in hippocampal network activity and the maturation of contextual learning.

Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice.

Insulin-like growth factor 2 (IGF2) was recently found to play a critical role in memory consolidation in rats and mice, and hippocampal or systemic administration of recombinant IGF2 enhances memory. Here, using a gene therapy-based approach with adeno-associated virus (AAV), we show that IGF2 overexpression in the hippocampus of aged wild-type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF2 expression decreases in the hippocampus of patients with Alzheimer's disease, and this leads us to hypothesize that increased IGF2 levels may be beneficial for treating the disease. Thus, we used the AAV system to deliver IGF2 or IGF1 into the hippocampus of the APP mouse model Tg2576 and demonstrate that IGF2 and insulin-like growth factor 1 (IGF1) rescue behavioural deficits, promote dendritic spine formation and restore normal hippocampal excitatory synaptic transmission. The brains of Tg2576 mice that overexpress IGF2 but not IGF1 also show a significant reduction in amyloid levels. This reduction probably occurs through an interaction with the IGF2 receptor (IGF2R). Hence, IGF2 and, to a lesser extent, IGF1 may be effective treatments for Alzheimer's disease.

Connexin 30 sets synaptic strength by controlling astroglial synapse invasion

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.

Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats.

In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals. However, whether this enhancement also occurs in old rats, when cognitive impairment is ameliorated by GH and IGF-I (des-IGF-I), remains to be determined. To address this issue, we used an in vitro CA1 hippocampal slice preparation and extracellular recording techniques to study the effects of acute application of GH and IGF-I on compound field excitatory postsynaptic potentials (fEPSPs), as well as AMPA- and NMDA-dependent fEPSPs, in young adult (10months) and old (28months) rats. The results indicated that both GH and IGF-I increased compound-, AMPA-, and NMDA-dependent fEPSPs to a similar extent in slices from both age groups and that this augmentation was likely mediated via a postsynaptic mechanism. Initial characterization of the signaling cascades underlying these effects revealed that the GH-induced enhancement was not mediated by the JAK2 signaling element in either young adult or old rats but that the IGF-I-induced enhancement involved a PI3K-mediated mechanism in old, but not young adults. The present findings are consistent with a role for a GH- or IGF-I-induced enhancement of glutamatergic transmission in mitigating age-related cognitive impairment in old rats.