Modulation of LTP

1. Leung et al., 2003

   Anmerkungen:

   • in freely moving rats these effects depend on the behavioral state of the animal
   • Basal LTP in the immobile or sleeping rat is not affected by muscarinic antagonists; but if tetanic stimulation is delivered to the Schaffer-commissural projection when the animal is generating cholinergically driven theta activity as it moves around its environment, an enhanced level of LTP is induced in area CA1.
2. reviewed in Segal and Auerbach, 1997
   1. inhibition of LTP by broad-spectrum muscarinic antagonists
      1. injection into the medial septum

         Anmerkungen:

         • of the neurotoxin immunoglobulin G (IgG)-saporin >> reduced LTP to baseline
   2. reduction in the threshold for LTP by muscarinic agonists or by stimulation of the septum
3. mechanism
   1. Segal and Auerbach, 1997
      1. high-affinity postsynaptic M2
      2. activation of M2

         Anmerkungen:

         • Activation of muscarinic receptors in the hippocampus leads to G protein-mediated block of a number of K channels, including IAHP, IM, and IL, as well as enhanced NMDA receptor function

1. 5-HT
   1. depletion of serotonin reduced the magnitude of LTP in the dentate gyrus in vivo
   2. At commissural- associational synapses in area CA3 in vitro, bath application of 5-HT was reported to inhibit LTP
   3. selective antagonist of 5-HT3 receptors, significantly enhanced the magnitude of LTP in area CA1 in the freely moving rat

      Anmerkungen:

      • by suppressing the excitability of interneurons mediating feedforward inhibition
2. NA
   1. Depletion in DG- reduction in LTP magnitude
   2. promote late LTP

      Anmerkungen:

      • injection of glutamate produces a delayed protein synthesis-dependent potentiation of perforant path-evoked responses in the dentate gyrus
3. DA
   1. role in the induction of protein synthesis-dependent L-LTP in area CA1
      1. Knockout of the D1 dopamine receptor

         Anmerkungen:

         • produces mice that lack L-LTP while displaying normal E-LTP (
      2. dopaminergic antagonists

         Anmerkungen:

         • block L-LTP when given during, but not after, a strong tetanus applied to induce L-LTP
   2. CA1- enhancement of LTP in novel environments

1. role in LTP induction
   1. BDNF null mice

      Anmerkungen:

      • LTP is impaired in BDNF-null mice (Korte et al., 1995), and the deficit can be rescued in vitro by BDNF administered directly (Patterson et al., 1996) or by viral transfection (Korte et al., 1996).
2. Can produce LTP
   1. CA1- slow onset LTP
   2. dentate gyrus- rapid onset LTP

1. IL-1 reduces mossy fiber LTP
2. Reduces NMDA receptor-dependent LTP in area CA1 and the dentate gyrus
3. functional implications- produced in

   Anmerkungen:

   • this may partly account for the neurodegeneration and cognitive deficits sometimes observed in such circumstances
   1. aging
   2. stress
4. induction of LTP
   1. knockouts

      Anmerkungen:

      • IL-1 receptor knockout have suggested that IL-1 may be required for the induction of LTP under physiological conditions

Anmerkungen:

• See stress essay

1. Rapid-
   1. facilitates LTP
   2. Mineralocorticoid Receptors (MRs)
      1. Karst et al (2005)

         Anmerkungen:

         •    suggested that Corticosterone enhances LTP via MRs. These receptors were found to be activated only when levels of Corticosteroids are high, meaning that they could serve as a ‘hormone sensor’, which acts quickly to the dramatic elevation of stress hormones.   
   3. via interactio with NAs
   4. Evidence
      1. (+)
         1. Pu et al (2007)

            Anmerkungen:

            • In the DG in the Hippocampus, in-vitro experiments by Pu et al (2007) showed that when co-applied, Corticosterone and ISO facilitated early and late phases of LTP
         2. Wiegert et al, 2006

            Anmerkungen:

            • Hippocampus CA1 regions Corticosterone can enhance LTP via non-genomic mechanisms if applied no more than 10 minutes prior to High-Frequency Stimulation 
            1. co-applied

               Anmerkungen:

               •    the effects seemed additive because they enhanced both early and late phase LTP. This could suggest the importance of the combination of the hormones in the stress response as they further facilitate LTP and consolidate memory.   
      2. (-)
         1. Pu et al (2009)

            Anmerkungen:

            • didn’t find evidence of fast non-genomic actions of Corticosterone in the Basolateral Amygdala (BLA). 
            1. saturation of LTP

               Anmerkungen:

               • facilitation of ISO on LTP has been very fast acting and reached maximal potentiation and therefore the actions of Corticosterone couldn’t have been observed
            2. MRs already activated

               Anmerkungen:

               • the animal slices prepared had already activated MRs, so presumably Corticosterone occupied the GRs and wouldn’t have mediated any fast non-genomic actions by the MRs
            3. In-vitro

               Anmerkungen:

               •    Finally, as the experiment was conducted in-vitro it’s possible it didn’t take into account a network of other hormones and connected brain regions.   
2. Slow-
   1. Glucocorticoid Receptors (GRs)
   2. attenuates LTP
3. 3 temporal domains

   Anmerkungen:

   •    It is thought that there can be interaction between these temporal domains, or that one effect in a temporal domain can lead to another. For example, acute stress mediators such as Noradrenaline (NA), act quickly to respond to the ongoing threat by increasing heart rate, vigilance and other mechanisms that promote optimal functioning. However, it has been shown that it also leads to slower gene-mediated mechanism that lead to long-term changes which are thought to consolidate the information from the stress event.   
   1. synaptic effects- ms-min
   2. transcriptions- min-hr
   3. genomic/ structural- hr-days-months
4. Evidence
   1. Alfarez et al, 2003

      Anmerkungen:

      • Individually, NA facilitates LTP when applied just before the stimulation of LTP, and Corticosterone (A Corticosteroid present in animals) attenuates LTP when applied over 24 hours before the stimulation of LTP 
      1. NA- rapid- facilitates LTP
      2. cortico-slow- attenuates LTP
   2. Joels & de Kloet, 1989

      Anmerkungen:

      • In the Hippocampus when a GR agonist was applied about an hour before NA, it attenuated the excitability caused by NA 
      1. GR agonist- slow- attenuates the facilitation by NA
   3. Pu et al., 2007

      Anmerkungen:

      • This slow mediated response has been continuously replicated in many different studies, and recently has also been shown to happen in the in the Dentate Gyrus (DG) 
      1. DG
         1. co-application of Cortico and adrenoceptor agonist

            Anmerkungen:

            • facilitated early and late phases of LTP
         2. rapid- cortcico + tetanus (together)- no affect

            Anmerkungen:

            • corticosterone was applied with TBS- no sig affect on LTP
         3. rapid- with bicuculline

            Anmerkungen:

            • a GABA receptor antagonist- to reduce the supression provided by GABAergic transmission corticosterone was administered just before and during TBS with bicuculline >>significant enhancement in early, but not lay phase LTP
         4. NA enhanced late LTP
   4. Pu et al, 2009
      1. amygdala

         Anmerkungen:

         • when Corticosterone was applied more than 2 hours in advance of an adrenoceptor agonist Isoproterenol (ISO) and LTP stimulation, it inhibited the facilitatory actions of ISO on LTP
         1. Cotrico- slow- attenuates LTP

            Anmerkungen:

            • corticosterone was applied 2h before TBS and adrenoceptor agonist ISO>> inhibited facilitatory actions of ISO on LTP
5. NA and Cortico- Additive mechanism

   Anmerkungen:

   •    In the rapid mode Corticosteroids and NA target different mechanisms, GluA2 and GluA1 respectively (See figure 2). This suggests that the effects are more additive than synergistic, because they don’t target the same intracellular mechanism. This theory is also supported by observations seen by Pu et al (2007). In his experiments when they were applied individually just before LTP stimulation, NA enhaced late phase LTP, and Corticosterone enhanced early phase LTP more significantly (but only in the presence of bicuculline), and was also observed by Wiegert et al (2006). When co-applied the effects seemed additive because they enhanced both early and late phase LTP. This could suggest the importance of the combination of the hormones in the stress response as they further facilitate LTP and consolidate memory.   

Anlagen:

• Endocannabinoids in synaptic plasticity

1. Endogenous CB release modulates inhibitory transmission
2. CB release modulates LTP induction
3. CB signalling

1. Morphological plasticity
   1. Ullian et al. (2001)

      Anmerkungen:

      • increased number of functional synapses are formed in the presence of glia. These effects were thought to be due to diffusible factors released by glial cells
      1. increase in synapses
   2. Christopherson et al., 2005

      Anmerkungen:

      • A family of extracellular matrix proteins called thrombospondins were shown to be released from astrocytes in culture and to increase expression of pre- and post-synaptic proteins in RGC cultures
      1. thrombospondins- increase expression of synaptic proteins

         Anmerkungen:

         • A family of extracellular matrix proteins called thrombospondins were shown to be expressed astrocytes
      2. thrombospondins knockout mice
         1. had fewer synapses than controls
   3. Murai et al. (2003)

      Anmerkungen:

      • found that ephrin-A3 was expressed on astrocytic processes in the hippocampus. Expression of ephrin-A3 by glia serves to negatively regulate dendritic spine expansion. Therefore, when astrocytes do not surround a dendritic spine, they do not make the necessary contact to initiate Eph signaling, thereby allowing further elaboration of the spine. This work suggests an ability of glia to directly regulate morphological plasticity in the intact brain.

Anmerkungen:

•  are themselves also plastic and can change in response to neuronal activity

1. presynaptic function
   1. Oliet et al. (2001)

      Anmerkungen:

      • In virgin rats, where synapses are tightly ensheathed by glia, blockade of glial glutamate transporters decreased the amplitude of evoked currents and increased paired-pulse facilitation (PPF) ratio
2. Hippocampus
   1. anatomical evidence

      Anmerkungen:

      • hippocampal astrocytes contact thousands of synapses (Bushong et al., 2002) and that they are connected together to form large, interconnected networks
   2. glial glutamate release
      1. Araque et al., 1998

         Anmerkungen:

         • action potential-evoked synaptic transmission was depressed following astrocyte stimulation. This depression involved an increase in glial intracellular Ca2+ since it was blocked by BAPTA injection in astrocytes
         1. blocks synaptic transmission
   3. inhibitory interneurons

      Anmerkungen:

      • interneurons synapse onto principal neurons of the hippocampus and provide GABA-mediated inhibitory input
      1. Kang et al., 1998

         Anmerkungen:

         • stimulation of astrocytes located in close proximity to interneurons could, in turn, stimulate these interneurons through glutamate release
         • This stimulation resulted in increased frequency of miniature inhibitory post-synaptic currents recorded in pyramidal neurons. They also showed that astrocytes could be activated directly by GABA release from interneurons acting on glial GABAbreceptors
         1. application of GABAb antagonists

            Anmerkungen:

            • disrupted potentiation of inhibitory synaptic transmission
         2. glia-interneuron to pyramidal neuron loop

            Anmerkungen:

            • These data suggest that GABAergic activation of astrocytes potentiates inhibitory synaptic activity through a glia-interneuron to pyramidal neuron loop
            1. Liu et al., 2004
               1. mediated by kainate receptors

                  Anmerkungen:

                  • mediated by astrocytic glutamate signaling to kainate interneuronal receptors
   4. CA3–CA1 hippocampal synapses

      Anmerkungen:

      • Theory based on this evidence-  homosynaptic modulation and plasticity that occur locally probably involve a small number of astrocytes and do not require communication within a glial network, whereas, heterosynaptic plasticity phenomena are based upon glial communication that occurs throughout a glial syncitium. Although the mechanisms involved in these two studies are different, they suggest that glial cells are essential elements of hippocampal plasticities.
      1. Zhang et al., 2003
         1. depression of transmitter release- glial-mediated

            Anmerkungen:

            • this depression was indeed a glial-mediated mechanism since it was abolished in the presence of glial inhibitors (fluoroacetate and octanol) or in the absence of glial cells in culture preparations
         2. glutamate induced intracellular calcium rises in glial cells, triggering ATP release.

            Anmerkungen:

            • This extracellular ATP acted homo- and heterosynaptically to induce pre-synaptic suppression.
      2. Serrano et al., 2003

         Anmerkungen:

         • This suggests that glial cells not only act as complementary elements in neuronal modulation, but are an integrated and necessary components in network plasticity
         1. tetanus stimuli-recruits interneurons through NMDA receptors and induces GABA release

            Anmerkungen:

            • Surrounding glial cells show a calcium-dependent activation via GABAb receptors. It is thought that the Ca2+increase induces ATP release from glial cells, which degrades into adenosine
         2. adenosine, acting through A1 receptors, heterosynaptically induces depression on Schaffer collaterals
            1. Ca increase>> ATP release from glial>> degraded into adenosine
         3. blocking Ca2+-mediated activation of glial cells disrupted the heterosynaptic depression of Schaffer collateral synapses
      3. evidence for glial cells in heterosynaptic plasticity

1. Two signaling pathways

   Anmerkungen:

   • which glial cells can modulate NMDA-dependent glutamatergic transmission
   1. D-serine

      Anmerkungen:

      •  d-serine, a co-agonist acting on the glycine site at NMDA-type glutamate receptors, known to be necessary for the induction of hippocampal LTP
      1. Yang et al., 2003

         Anmerkungen:

         • in the hippocampus- glial release of d-serine was necessary to induce NMDA-type LTP
         1. glial release D-serine- LTP induction

            Anmerkungen:

            • D-serine enhanced NMDA receptor activation and enabled LTP induction in glial conditioned medium cultures
         2. LTP suppressed by NMDAR anta, glycine-binding-site blockers of NMDAR, or an enzyme that degrades endogenous D-serine
   2. TNFα

      Anmerkungen:

      • a protein that increases surface expression of neuronal AMPA receptors
      1. TNFα, released by glial cells, increases synaptic efficacy
2. glial specific knockout
   1. McCall et al., 1996; Nishiyama et al., 2002

      Anmerkungen:

      • LTP was modified