Facilitation of corticostriatal plasticity by the amygdala requires Ca2+-induced Ca2+ release in the ventral striatum.

Motor learning and habit formation are thought to depend on corticostriatal synaptic plasticity. Moreover, basolateral amygdala (BLA) activity facilitates consolidation of striatal-dependent memories. Accordingly, BLA stimulation in vitro facilitates long-term potentiation (LTP) induction at corticostriatal synapses onto medium spiny neurons (MSNs). Although these effects were found to depend on N-methyl-d-aspartate (NMDA) receptor activation at BLA synapses and consequent Ca(2+) influx, it is unclear how this event can facilitate LTP at cortical synapses, even when the two inputs are not coactivated. Here, we aimed to shed light on this question, using whole cell recordings of MSNs in vitro. We first tested whether BLA inputs end at more proximal dendritic sites than cortical inputs. In this scenario, BLA synapses would experience stronger spike-related depolarizations and be in a strategic position to control the spread of second messengers. However, comparison of compound excitatory postsynaptic potentials and single-axon excitatory postsynaptic currents revealed that BLA and cortical synapses are intermingled. Next, we examined the sensitivity of cortical and BLA NMDA responses to ifenprodil because NR2A-containing NMDA receptors have faster kinetics than those containing NR2B subunits. However, the two inputs did not differ in this respect. Last, reasoning that propagating waves of Ca(2+)-induced Ca(2+) release (CICR) could bridge temporal gaps between the two inputs, we tested the effects of CICR inhibitors on the BLA facilitation of corticostriatal LTP induction. Pharmacological interference with CICR blocked corticostriatal LTP induction. Thus our results are consistent with the notion that NMDA-dependent Ca(2+) influx at BLA synapses initiates propagating waves of CICR, thereby biasing active corticostriatal inputs toward synaptic potentiation.

Age- and region-dependent patterns of Ca2+ accumulations following status epilepticus.

Elevated Ca(2+) concentrations have been implicated in cell death mechanisms following seizures, however, the age and brain region of intracellular Ca(2+) accumulations [Ca(2+)](i), may influence whether or not they are toxic. Therefore, we examined regional accumulations of (45)Ca(2+) by autoradiography from rats of several developmental stages (P14, P21, P30 and P60) at 5, 14, and 24h after status epilepticus. To determine whether the uptake was intracellular, Ca(2+) was also assessed in hippocampal slices with the dye indicator, Fura 2AM at P14. Control animals accumulated low homogeneous levels of (45)Ca(2+); however, highly specific and age-dependent patterns of (45)Ca(2+) uptake were observed at 5h. (45)Ca(2+) accumulations were predominant in dorsal hippocampal regions, CA1/CA2/CA3a, in P14 and P21 rats and in CA3a and CA3c neurons of P30 and P60 rats. Selective midline and amygdala nuclei were marked at P14 but not at P21 and limbic accumulations recurred with maturation that were extensive at P30 and even more so at P60. At 14 h, P14 and P21 rats had no persistent accumulations whereas P30 and P60 rats showed persistent uptake patterns within selective amygdala, thalamic and hypothalamic nuclei, and other limbic cortical regions that continued to differ at these ages. For example, piriform cortex accumulation was highest at P60. Fura 2AM imaging at P14 confirmed that Ca(2+) rises were intracellular and occurred in both vulnerable and invulnerable regions of the hippocampus, such as CA2 pyramidal and dentate granule cells. Silver impregnation showed predominant CA1 injury at P20 and P30 but CA3 injury at P60 whereas little or no injury was found in extrahippocampal structures at P14 and P20 but was modest at P30 and maximal at P60. Thus, at young ages there was an apparent dissociation between high (45)Ca(2+) accumulations and neurotoxicity whereas in adults a closer relationship was observed, particularly in the extrahippocampal structures.

Extracellular diffusion in laminar brain structures exemplified by hippocampus.

Numerous brain structures are composed of distinct layers and such stratification has a profound effect on extracellular diffusion transport in these structures. We have derived a more general form of diffusion equation incorporating inhomogeneities in both the extracellular volume fraction (α) and diffusion permeability (θ). A numerical solution of this equation for a special case of layered environment was employed to analyze diffusion in the CA1 region of hippocampus where stratum pyramidale occupied by the bodies of principal neurons is flanked by stratum radiatum and stratum oriens. Extracellular diffusion in the CA1 region was measured in vitro by real-time iontophoretic and real-time pressure methods, and numerical analysis found that stratum pyramidale had a significantly smaller extracellular volume fraction (α=0.127) and lower diffusion permeability (θ=0.327) than the other two layers (α=0.218, θ=0.447). Stratum pyramidale thus functioned as a diffusion barrier for molecules attempting to cross it. We also demonstrate that unless the detailed properties of all layers are taken into account when diffusion experiments are interpreted, the extracted apparent parameters of the extracellular space lose their physical meaning and capacity to describe any individual layer. Such apparent parameters depend on diffusion distance and direction, giving a false impression of microscopic anisotropy and non-Gaussian behavior. This finding has implications for all diffusion mediated physiological processes as well as for other diffusion methods including integrative optical imaging and diffusion-weighted magnetic resonance imaging.

NMDA-dependent facilitation of corticostriatal plasticity by the amygdala.

Emotions generally improve memory, and the basolateral amygdala (BLA) is believed to mediate this effect. After emotional arousal, BLA neurons increase their firing rate, facilitating memory consolidation in BLA targets. The enhancing effects of BLA activity extend to various types of memories, including motor learning, which is thought to involve activity-dependent plasticity at corticostriatal synapses. However, the underlying mechanisms are unknown. Here we show that the NMDA-to-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ratio is nearly twice as high at BLA as compared with cortical synapses onto principal striatal neurons and that activation of BLA inputs greatly facilitates long-term potentiation induction at corticostriatal synapses. This facilitation was NMDA-dependent, but it occurred even when BLA and cortical stimuli were 0.5 s apart during long-term potentiation induction. Overall, these results suggest that BLA activity opens long time windows during which the induction of corticostriatal plasticity is facilitated.