Dopaminergic Suppression of Synaptic Transmission in the Lateral Entorhinal Cortex

Dopaminergic projections to the superficial layers of the lateral entorhinal cortex can modulate the strength of olfactory inputs to the region. We have found that low concentrations of dopamine facilitate field EPSPs in the entorhinal cortex, and that higher concentrations of dopamine suppress synaptic responses. Here, we have used whole-cell current clamp recordings from layer II neurons to determine the mechanisms of the suppression. Dopamine (10 to 50 μM) hyperpolarized membrane potential and reversibly suppressed the amplitude of EPSPs evoked by layer I stimulation. Both AMPA- and NMDA-mediated components were suppressed, and paired-pulse facilitation was also enhanced indicating that the suppression is mediated largely by reduced glutamate release. Blockade of D2-like receptors greatly reduced the suppression of EPSPs. Dopamine also lowered input resistance, and reduced the number of action potentials evoked by depolarizing current steps. The drop in input resistance was mediated by activation of D1-like receptors, and was prevented by blocking K+ channels with TEA. The dopaminergic suppression of synaptic transmission is therefore mediated by a D2 receptor-dependent reduction in transmitter release, and a D1 receptor-dependent increase in a K+ conductance. This suppression of EPSPs may dampen the strength of sensory inputs during periods of elevated mesocortical dopamine activity

Adenosine A1 Receptor-Mediated Synaptic Depression in the Developing Hippocampal Area CA2

Immunolabeling for adenosine A1 receptors (A1Rs) is high in hippocampal area CA2 in adult rats, and the potentiating effects of caffeine or other A1R-selective antagonists on synaptic responses are particularly robust at Schaffer collateral synapses in CA2. Interestingly, the pronounced staining for A1Rs in CA2 is not apparent until rats are 4 weeks old, suggesting that developmental changes other than receptor distribution underlie the sensitivity of CA2 synapses to A1R antagonists in young animals. To evaluate the role of A1R-mediated postsynaptic signals at these synapses, we tested whether A1R agonists regulate synaptic transmission at Schaffer collateral inputs to CA2 and CA1. We found that the selective A1R agonist CCPA caused a lasting depression of synaptic responses in both CA2 and CA1 neurons in slices obtained from juvenile rats (P14), but that the effect was observed only in CA2 in slices prepared from adult animals (~P70). Interestingly, blocking phosphodiesterase activity with rolipram inhibited the CCPA-induced depression in CA1, but not in CA2, indicative of robust phosphodiesterase activity in CA1 neurons. Likewise, synaptic responses in CA2 and CA1 differed in their sensitivity to the adenylyl cyclase activator, forskolin, in that it increased synaptic transmission in CA2, but had little effect in CA1. These findings suggest that the A1R-mediated synaptic depression tracks the postnatal development of immunolabeling for A1Rs and that the enhanced sensitivity to antagonists in CA2 at young ages is likely due to robust adenylyl cyclase activity and weak phosphodiesterase activity rather than to enrichment of A1Rs

Dopaminergic modulation of entorhinal cortex function

The neurotransmitter dopamine has been shown to play an important role in the mnemonic functions of the prefrontal cortex, but it is unclear how dopamine may affect sensory and mnemonic processing in the entorhinal cortex. Midbrain dopamine neurons project to the superficial layers of the lateral entorhinal cortex and may modulate olfactory inputs that also terminate in this area. In awake rats, increasing extracellular dopamine levels in the entorhinal cortex with a selective dopamine reuptake inhibitor facilitated basal synaptic transmission in piriform cortex inputs to layer II. Experiments in slices of the entorhinal cortex maintained in vitro demonstrated concentration-dependent, bidirectional effects of dopamine on synaptic responses; a low 10 oM concentration of dopamine enhanced synaptic responses and higher concentrations of 50 and 100 oM dopamine suppressed responses. The facilitation of responses was dependent on activation of D 1 receptors and the suppression was dependent on D 2 receptors. Intracellular recordings of mixed and isolated synaptic responses demonstrated that the dopaminergic suppression is mediated by a D 2 receptor-dependent reduction in glutamate release and a D 1 -dependent drop in cellular input resistance. The drop in input resistance was mediated by a D 1 receptor-dependent K + conductance. In additional experiments, patterned stimulation of the piriform cortex that induces persistent changes in synaptic strength in the entorhinal cortex was used to assess the effects of dopamine on mechanisms of synaptic plasticity in awake rats. Long-term potentiation and depression were successfully induced in control animals, but the same stimulation protocols failed to alter synaptic function in animals treated with a dopamine reuptake inhibitor. The effects of depleting dopamine in the entorhinal cortex on olfactory memory were also assessed using an olfactory non-match-to-sample task. Rats with 6-OHDA lesions of the entorhinal cortex made more errors and took nearly twice as long to reacquire criterion performance relative to control animals during post-surgical retraining. However, once criterion performance was re-attained, the behavior of lesioned animals was indistinguishable from controls on a version of the task involving longer delay periods. These findings point to multiple mechanisms through which exposure to different concentrations of dopamine may modulate sensory and mnemonic processing by modulating synaptic transmission within the lateral entorhinal cortex

Parasubicular efferents to layer II of the entorhinal cortex : modulation of responses to piriform cortex inputs in vivo

Although a major output of the hippocampal formation is from the subiculum to the deep layers of the entorhinal cortex, the parasubiculum projects to the superficial layers of the entorhinal cortex, and may therefore modulate how the entorhinal cortex responds to sensory inputs from other cortical regions. Recordings at multiple depths in the entorhinal cortex were first used to characterize field potentials evoked by stimulation of the parasubiculum in urethane-anesthetized rats. Current source density analysis showed that a prominent surface-negative field potential component is generated by synaptic activation in layer II. The surface-negative field potential was also observed in rats with chronically implanted electrodes. The response was maintained during short stimulation trains of up to 125 Hz, suggesting that it is generated by activation of monosynaptic inputs to the entorhinal cortex. The piriform cortex also projects to layer II of the entorhinal cortex, and interactions between parasubicular and piriform cortex inputs were investigated using double-site stimulation tests. Simultaneous activation of parasubicular and piriform cortex inputs with high-intensity pulses resulted in smaller synaptic potentials than were expected on the basis of summing the individual responses, consistent with the termination of both pathways onto a common population of neurons. Paired-pulse tests were then used to assess the effect of parasubicular stimulation on responses to piriform cortex stimulation. Responses of the entorhinal cortex to piriform cortex inputs were inhibited when the parasubiculum was stimulated 5 ms earlier, and were enhanced when the parasubiculum was stimulated 20 to 150 ms earlier. These results indicate that excitatory inputs to the entorhinal cortex from the parasubiculum may enhance the propagation of neuronal activation patterns into the hippocampal circuit by increasing the responsiveness of the entorhinal cortex to appropriately timed inputs

New insights into the regulation of synaptic plasticity from an unexpected place:Hippocampal area CA2

The search for molecules that restrict synaptic plasticity in the brain has focused primarily on sensory systems during early postnatal development, as critical periods for inducing plasticity in sensory regions are easily defined. The recent discovery that Schaffer collateral inputs to hippocampal area CA2 do not readily support canonical activity-dependent long-term potentiation (LTP) serves as a reminder that the capacity for synaptic modification is also regulated anatomically across different brain regions. Hippocampal CA2 shares features with other similarly "LTP-resistant" brain areas in that many of the genes linked to synaptic function and the associated proteins known to restrict synaptic plasticity are expressed there. Add to this a rich complement of receptors and signaling molecules permissive for induction of atypical forms of synaptic potentiation, and area CA2 becomes an ideal model system for studying specific modulators of brain plasticity. Additionally, recent evidence suggests that hippocampal CA2 is instrumental for certain forms of learning, memory, and social behavior, but the links between CA2-enriched molecules and putative CA2-dependent behaviors are only just beginning to be made. In this review, we offer a detailed look at what is currently known about the synaptic plasticity in this important, yet largely overlooked component of the hippocampus and consider how the study of CA2 may provide clues to understanding the molecular signals critical to the modulation of synaptic function in different brain regions and across different stages of development

Induction of activity-dependent LTD requires muscarinic receptor activation in medial prefrontal cortex

The medial prefrontal cortex (mPFC) forms part of a neural circuit involved in the formation of lasting associations between objects and places. Cholinergic inputs from the basal forebrain innervate the mPFC and may modulate synaptic processes required for the formation of object-in-place memories. To investigate whether acetylcholine regulates synaptic function in the rat mPFC, whole-cell voltage-clamp recordings were made from pyramidal neurons in layer V. Bath application of the cholinergic agonist carbachol caused a potent and long-term depression (LTD) of synaptic responses that was blocked by the muscarinic receptor antagonist scopolamine and was mimicked, in part, by the M 1 receptor agonists McN-A-343 or AF102B. Furthermore, inhibition of PKC blocked carbachol-mediated LTD. We next determined the requirements for activity-dependent LTD in the prefrontal cortex. Synaptic stimulation that was subthreshold for producing LTD did, however, result in LTD when acetylcholine levels were enhanced by inhibition of acetylcholinesterase or when delivered in the presence of the M 1-selective positive allosteric modulator BQCA. Increasing the levels of synaptic stimulation resulted in M 1 receptor-dependent LTD without the need for pharmacological manipulation of acetylcholine levels. These results show that synaptic stimulation of muscarinic receptors alone can be critical for plastic changes in excitatory synaptic transmission in the mPFC. In turn, these muscarinic mediated events may be important in the formation of object-in-place memories. A loss of basal forebrain cholinergic neurons is a classic hallmark of Alzheimer's dementia and our results provide a potential explanation for the loss of memory associated with the disease

Postsynaptic Signals Mediating Induction of Long-Term Synaptic Depression in the Entorhinal Cortex

The entorhinal cortex receives a large projection from the piriform cortex, and synaptic plasticity in this pathway may affect olfactory processing. In vitro whole cell recordings have been used here to investigate postsynaptic signalling mechanisms that mediate the induction of long-term synaptic depression (LTD) in layer II entorhinal cortex cells. To induce LTD, pairs of pulses, using a 30-millisecond interval, were delivered at 1 Hz for 15 minutes. Induction of LTD was blocked by the NMDA receptor antagonist APV and by the calcium chelator BAPTA, consistent with a requirement for calcium influx via NMDA receptors. Induction of LTD was blocked when the FK506 was included in the intracellular solution to block the phosphatase calcineurin. Okadaic acid, which blocks activation of protein phosphatases 1 and 2a, also prevented LTD. Activation of protein phosphatases following calcium influx therefore contributes to induction of LTD in layer II of the entorhinal cortex

Inhibiting dopamine reuptake blocks the induction of long-term potentiation and depression in the lateral entorhinal cortex of awake rats

Synaptic plasticity in olfactory inputs to the lateral entorhinal cortex may result in lasting changes in the processing of olfactory stimuli. Changes in dopaminergic tone can have strong effects on basal evoked synaptic responses in the superficial layers of the entorhinal cortex, and the current study investigated whether dopamine may modulate the induction of long-term potentiation (LTP) and depression (LTD) in piriform cortex inputs to layer II of the lateral entorhinal cortex in awake rats. Groups of animals were pretreated with either saline or the selective dopamine reuptake inhibitor GBR12909 prior to low or high frequency stimulation to induce LTD or LTP. In saline-treated groups, synaptic responses were potentiated to 122.4 ± 6.4% of baseline levels following LTP induction, and were reduced to 84.5 ± 4.9% following induction of LTD. Changes in synaptic responses were maintained for up to 60 min and returned to baseline levels within 24 h. In contrast, induction of both LTP and LTD was blocked in rats pretreated with GBR12909. Dopaminergic suppression of synaptic plasticity in the entorhinal cortex may serve to restrain activity-dependent plasticity during reward-relevant behavioral states or during processing of novel stimuli

Caffeine-induced synaptic potentiation in hippocampal CA2 neurons

Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A 1 adenosine receptors (A 1 Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. We found that physiological doses of caffeine in vivo or A 1 R antagonists in vitro induced robust, long-lasting potentiation of synaptic transmission in rat CA2 without affecting other regions of the hippocampus

Choosing Among Alternative New Product Development Projects: The Role of Heuristics

The initial screening decision that marketing managers make is critical. It requires the selection of which innovation project to invest in, which is fundamental to marketing success. However, our knowledge of how managers make these decisions and how this impacts performance is limited. By drawing upon cognitive psychology and the managerial decision-making literature, we address two critical questions. The first question focuses on identifying specific decisionmaking types (e.g., specific heuristics, intuition) used when making an innovation-screening decision. Based on this analysis and prior research, we develop specific decision-maker profiles about how an individual manager decides. The second research question is about connecting these profiles with performance. Specifically, it addresses what the consequences of different decision-maker profiles are on the perceived accuracy and speed of decision-making? Data were collected from 122 senior managers in these industries. We find that when heuristics are used alone, or concurrently with intuition, managers make decisions that are as accurate as when they rely on analytical decision-making. However, the process is significantly faster. The findings provide an important step towards a more comprehensive understanding of decisionmaking at the front-end of innovation