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Long-term synaptic depression (LTD) in cortico-striatal circuits is initiated by depolarization of striatal medium spiny neurons through a convergent cortical glutamatergic input. This produces retrograde endocannabinoid signaling to presynaptic cortical terminals and eventually results in long term (>30 min) decreases in glutamate release. These same circuits can also undergo short-term depression (STD) through a less well-defined process in which the magnitude of postsynaptic responses returns to baseline levels within 10 min. Additionally, the cortico-striatal circuit shows characteristics of a GABA A receptor-dependent low-pass filter, which results in significant attenuation of high frequency cortical inputs. The majority of in vitro studies of LTD have used a 100-Hz induction paradigm and it is unclear whether other frequencies, which may also have physiological relevance, have equivalent ability to induce this form of plasticity. Here we have investigated the effectiveness of a range of induction paradigms in producing LTD in cortico-striatal circuits, and demonstrate that some lower frequency paradigms, with perhaps more physiological relevance, are more effective at inducing LTD. We also show that GABA A receptor-dependent frequency filtering in this circuit is altered following the induction of LTD and STD suggesting an important role for synaptic depression in signal processing in these circuits. [ABSTRACT FROM AUTHOR]

Abstract: Genes and environmental conditions interact in the development of cognitive capacities and each plays an important role in neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. We utilized mice heterozygous for a Snap25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. We show that SNAP-25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, we examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. We found that prenatal exposure to nicotine in Snap25 heterozygote null mice produced a deficit in the D2R-dependent induction of LTD, although CB1R regulation of plasticity was not impaired. We also show that prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null Snap25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene×environmental influences can interact to perturb neural functions that regulate behavior. [Copyright &y& Elsevier]

Abstract: The phenomenon whereby the relative timing between presynaptic and postsynaptic spiking determines the direction and extent of synaptic changes in a critical temporal window is known as spike timing-dependent synaptic plasticity (STDP). We have previously reported that STDP profiles can be classified into two types depending on their layer-specific location along CA1 pyramidal neuron dendrites in the rat hippocampus, suggesting that there are differences in information processing between the proximal dendrite (PD) and distal dendrite (DD). However, how the different types of information processing interact at different dendritic locations remains unclear. To investigate how the temporal information of inputs to PD influences information processing at DD, PD stimulation was applied while the STDP protocol was simultaneously applied at DDs of CA1 pyramidal neurons. Synaptic plasticity induced by the STDP protocol at DDs was enhanced or depressed depending on the timing of the back-propagating action potentials (bAPs) and the excitatory and inhibitory postsynaptic potentials elicited by PD stimulation. These results suggested that bAPs function as carriers of temporal information of PD inputs to DD. Next, the influence of DD on PD was investigated using the same protocol. Synaptic plasticity at PD was modulated only if the pairing stimuli were applied to elicit coincidental timing of bAP and the excitatory postsynaptic potential. Such coding modulations could provide the basis for a novel learning rule and may be important factors in the integration of spatiotemporal input information in neural networks in the brain. [Copyright &y& Elsevier]

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates the induction of long-term potentiation (LTP), a possible cellular mechanism for learning. This study was undertaken to determine the effects of activation of nAChRs by nicotine on long-term plasticity in the songbird zebra finch, which is a valuable model to study synaptic plasticity and its implications to behavioral learning. Electrophysiological recordings in the robust nucleus of the archistriatum (RA) in adult zebra finch brain slices reveal that tetanic stimulation alone does not produce LTP. However, LTP is induced by such stimulation in the presence of nicotine. The nicotine-mediated LTP is blocked by dihydro-β-erythroidine (DHβE, 1 μM), an antagonist having a greater effect against nAChRs containing the alpha 4 subunit. In the presence of methyllcaconitine (MLA, 10 nM), an antagonist of nAChRs containing the alpha 7 subunit, a long-term depression (LTD) is unmasked, implicating a bi-directional type of plasticity in the zebra finch RA, which is modulated by differential activation of nAChR subtypes. Intracellular recordings from single neurons show a depression of the afterhyperpolarization (AHP) and an increase in frequency of evoked and spontaneous action potentials in the presence of nicotine. These results suggest that nicotinic cholinergic mechanisms may play a critical role in synaptic plasticity in the zebra finch song system and thereby influence song learning and plasticity. [Copyright &y& Elsevier]

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83±10%, n=5, P<0.01, compared with controls of 160±11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63±1% at 100 ng/ml, n=5 and 66±1% at 200 ng/ml, n=4, compared to controls of 56±6%, n=6). Manumycin A (2μM) had no effect on LTP (162±2%, n=5, compared to controls of 167±13%, n=5), but significantly attenuated LTD (88±6%, n=5, P<0.01, compared to controls of 63±9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240±40%, n=5, P<0.01, compared with controls of 100±4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92±2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP. [Copyright &y& Elsevier]