Distinct trafficking and expression mechanisms underlie LTP and LTD of NMDA receptor‐mediated synaptic responses

Although an increasing number of studies have demonstrated the plasticity of NMDA receptor‐mediated synaptic transmission, little is known about the molecular mechanisms that underlie this neurologically important process. In a study of NMDAR‐mediated synaptic responses in hippocampal Schaffer‐CA1 synapses whose AMPA receptor (AMPAR) activity is totally blocked, we uncovered differences between the trafficking mechanisms that underlie the long‐term potentiation (LTP) and long‐term depression (LTD) that can be induced in these cells under these conditions. The LTP‐producing protocol failed to induce a change in the amplitude of NMDAR‐mediated postsynaptic currents (NMDAR EPSCs) in the first 5–10 min, but induced gradual enhancement of NMDAR EPSCs thereafter that soon reached a stable magnitude. This “slow” LTP of NMDAR EPSCs (LTP_NMDA) was blocked by inhibiting exocytosis or actin polymerization in postsynaptic cells. By contrast, LTD of NMDAR EPSCs (LTD_NMDA) was immediately inducible, and, although it was blocked by the actin stabilizer, it was unaffected by exocytosis or endocytosis inhibitors. Furthermore, concomitant changes in the decay time of NMDAR EPSCs suggested that differential switches in NR2 subunit composition accompanied LTP_NMDA and LTD_NMDA, and these changes were blocked by the calcium buffer BAPTA or an mGluR antagonist. Our results suggest that LTP_NMDA and LTD_NMDA utilize different NMDAR trafficking pathways and express different ratios of NMDAR subunits on the postsynaptic surface. © 2009 Wiley‐Liss, Inc.     

Dopamine D1/D5 receptor signaling regulates synaptic cooperation and competition in hippocampal CA1 pyramidal neurons via sustained ERK1/2 activation

Synaptic cooperation and competition are important components of synaptic plasticity that tune synapses for the formation of associative long‐term plasticity, a cellular correlate of associative long‐term memory. We have recently reported that coincidental activation of weak synapses within the vicinity of potentiated synapses will alter the cooperative state of synapses to a competitive state thus leading to the slow decay of long‐term plasticity, but the molecular mechanism underlying this is still unknown. Here, using acute hippocampal slices of rats, we have examined how increasing extracellular dopamine concentrations interact and/or affect electrically induced long‐term potentiation (LTP) in the neighboring synapses. We demonstrate that D1/D5‐receptor‐mediated potentiation at the CA1 Schaffer collateral synapses differentially regulates synaptic co‐operation and competition. Further investigating the molecular players involved, we reveal an important role for extracellular signal‐regulated kinases‐1 and 2 (ERK1/2) as signal integrators and dose‐sensors. Interestingly, a sustained activation of ERK1/2 pathway seems to be involved in the differential regulation of synaptic associativity. The concentration‐dependent effects of the modulatory transmitter, as demonstrated for dopaminergic signaling in the present study, might offer additional computational power by fine tuning synaptic associativity processes for establishing long‐term associative memory in neural networks. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Adenosine A2A receptors modulate the dopamine D2 receptor‐mediated inhibition of synaptic transmission in the mouse prefrontal cortex

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D₁‐ and D₂‐like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A_2A receptors (A_2AR) also control PFC‐related responses and A_2AR antagonists are potential anti‐psychotic drugs. As tight antagonistic A_2AR–D₂R and synergistic A_2AR–D₁R interactions occur in other brain regions, we now investigated the crosstalk between A_2AR and D₁/D₂R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired‐pulse responses. Dopamine inhibition was prevented by the D₂R‐like antagonist sulpiride but not by the D₁R antagonist SCH23390 and was mimicked by the D₂R agonist sumanirole, but not by the agonists of either D₄R (A‐412997) or D₃R (PD128907). Dopamine inhibition was prevented by the A_2AR antagonist, SCH58261, and attenuated in A_2AR knockout mice. Accordingly, triple‐labelling immunocytochemistry experiments revealed the co‐localization of A_2AR and D₂R immunoreactivity in glutamatergic (vGluT1‐positive) nerve terminals of the PFC. This reported positive A_2AR–D₂R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti‐psychotic potential of A_2AR antagonists.     

β‐amyloid and ATP‐induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type‐5 receptors

β‐Amyloid (Aβ) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Aβ plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Aβ oligomers on the plasma membrane of astrocytes. The resulting aggregates of Aβ oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Aβ oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co‐cultured with astrocytes. This effect, which is purinergic receptor‐dependent, was not observed in pure neuronal cultures. Thus, Aβ oligomer‐ and mGluR5‐dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673–1686     

Modulation of defensive responses and anxiety-like behaviors by group I metabotropic glutamate receptors located in the dorsolateral periaqueductal gray

Glutamatergic neurotransmission in the dorsolateral periaqueductal gray (dlPAG) is related to defensive responses. However, the role of group I glutamate metabotropic receptors (mGluR) in these responses has been poorly investigated. The objective of the present study, therefore, was to test the hypothesis that interference with group I mGluR-mediated neurotransmission in dlPAG could modulate defensive responses. Male Wistar rats with cannulae aimed at the dlPAG were submitted to the following experiments: 1. intra dlPAG injections of vehicle (veh, 0.2 microL) or (RS)1-aminoindan-1,5-dicarboxylic acid (AIDA, 30-100 nmol, an mGluR1 receptor competitive antagonist) followed, 5 min later, by veh or trans-(+)-1-amino-1,3-ciclopentanedicarboxylic acid (tACPD, a group I and II mGluR agonist, 30 nmol); 2. intra-dlPAG injections of veh, AIDA (30 nmol) or 2-methyl-6-(phenylethynyl)-pyridine (MPEP, an mGluR5 receptor non-competitive antagonist, 50 nmol) followed by trans-azetidine-2,4-dicarboxylic acid (tADA, a group I mGluR agonist, 10 nmol); 3. and 4. intra-dlPAG injections of vehicle, AIDA (10-30 nmol) or MPEP (10-50 nmol) before the elevated plus maze (EPM) test; 5. intra-dlPAG injections of vehicle, AIDA (30 nmol) or MPEP (50 nmol) before the Vogel punished licking test. tACPD induced defensive responses characterized by jumps and an increased number of crossings in the observation box. These responses were attenuated by AIDA (30 nmol). tADA produced similar responses, although of lower intensity. tADA effects were prevented by AIDA and MPEP. Both drugs also produced anxiolytic-like effects in the EPM and Vogel tests when injected alone. The results suggest that group I metabotropic glutamate receptors in the dlPAG facilitate defensive responses and may also be involved in regulating anxiety-like behavior.     

Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor‐mediated signaling in roman high‐ and roman low‐avoidance rats

The Roman high (RHA)‐ and low (RLA)‐avoidance rat sublines have been identified as an addiction‐prone and addiction‐resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Δ⁹‐tetrahydrocannabinol (THC) on dopamine D_2/3 receptor (D_2/3R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB₁R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D_2/3R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D_2/3R, as evidenced by a supersensitive psychomotor response to the D_2/3R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug‐seeking, RLAs may exhibit a heightened proneness to cannabinoid drug‐seeking as compared to RHA rats.     

Contribution of estrogen receptor subtypes,ERα, ERβ, and GPER1 in rapid estradiol‐mediated enhancement of hippocampal synaptic transmission in mice

Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. This study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3–5‐month‐old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10–16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3‐CA1 synaptic contacts before and following application of 17β‐estradiol‐3‐benzoate (EB, 100 pM), the G‐protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 µM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB‐mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT and DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal‐regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes. © 2015 Wiley Periodicals, Inc.     

Priming of long-term potentiation by prior activation of group I and II metabotropic glutamate receptors in the rat dentate gyrus in vitro

The role of metabotropic glutamate receptors (mGluRs) in long-term potentiation (LTP) has remained controversial. However, it has recently been shown that group I mGluR activation, prior to high frequency stimulation (HFS), can facilitate or ‘prime' LTP in the area CA1 of the hippocampus. Here we report that, in the dentate gyrus in vitro, activation of both group I and group II mGluRs primes LTP. Control LTP, 60 min after HFS was 145.4±3.6% of control. The group I mGluR agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 100 μM), resulted in LTP of 180.1±12.1% of control, which was significantly greater than control LTP (n=4; P<0.05). The group I/II mGluR agonist 1S,3R-1-aminocyclopentate-1,3-dicarboxylic acid (1S,3R-ACPD, 10 μM), and the group II mGluR agonist (2S,3S,4S)-α-(carboxy-cyclopropyl)-glycine (L-CCG-1, 20 μM) also produced LTP that was significantly greater than control LTP (177.7±11.5% and 183.2±9.1% of control respectively; n=5; P<0.05). The group III mGluR agonist -2-amino-4-phosphonobutyric acid (L-AP4, 20 μM), failed to significantly prime LTP (153.8±5.9% of control; n=5). It also proved difficult to depotentiate the primed LTP. Following low frequency stimulation (LFS), control LTP was reduced to 101.1±3.6% of control, and to 145.0±2.1%, 141.2±14.7% and 134.0±8.7% of control for CHPG, ACPD and L-CCG-1 primed LTP respectively. We conclude that LTP may be primed by mGluR activation in the dentate gyrus and that this priming is mediated through group I and II mGluRs.     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.