5-HT4-Receptors Modulate Induction of Long-Term Depression but Not Potentiation at Hippocampal Output Synapses in Acute Rat Brain Slices

<div><p>The subiculum is the principal target of CA1 pyramidal cells and mediates hippocampal output to various cortical and subcortical regions of the brain. The majority of subicular pyramidal cells are burst-spiking neurons. Previous studies indicated that high frequency stimulation in subicular burst-spiking cells causes presynaptic NMDA-receptor dependent long-term potentiation (LTP) whereas low frequency stimulation induces postsynaptic NMDA-receptor-dependent long-term depression (LTD). In the present study, we investigate the effect of 5-hydroxytryptamine type 4 (5-HT4) receptor activation and blockade on both forms of synaptic plasticity in burst-spiking cells. We demonstrate that neither activation nor block of 5-HT4 receptors modulate the induction or expression of LTP. In contrast, activation of 5-HT4 receptors facilitates expression of LTD, and block of the 5-HT4 receptor prevents induction of short-term depression and LTD. As 5-HT4 receptors are positively coupled to adenylate cyclase 1 (AC1), 5-HT4 receptors might modulate PKA activity through AC1. Since LTD is blocked in the presence of 5-HT4 receptor antagonists, our data are consistent with 5-HT4 receptor activation by ambient serotonin or intrinsically active 5-HT4 receptors. Our findings provide new insight into aminergic modulation of hippocampal output.</p></div

Synaptic and membrane properties of BS-cells in the subiculum before and after application of 5-HT4 receptor ligands.

<p>Data given as means ± SEM.</p

5-HT4 receptors modulate LTD.

<p>A1: LFS induces LTD under control conditions. A2: Activation of 5-HT4-receptors significantly facilitates LTD. A3/4: Blockade of 5-HT4-receptors through RS 39604 or GR 113808 prevented LTD. B: Summary of changes in synaptic strength illustrated in A1-4. The antagonist GR 13808 is not included in the ANOVA. C: Averaged time courses of normalized EPSP responses during LFS. Control: white circles, RS 67333: black circles, RS 39604: gray circles, GR 113808: dark gray squares. D1: The PKA inhibitor H 89 prevented LTD under control conditions. D2: H 89 prevented LTD even in the presence of the 5-HT4 receptor agonist RS 67333. E: A 5-HT4 receptor agonist failed to modulate NMDA receptor mediated EPSPs during 30 minutes wash-in. Scale bars: 2 mV and 20 ms (A,D), 1 mV and 20 ms (E).</p

Effect of 5-HT4 receptors on synaptic and intrinsic properties of subicular BS neurons.

<p>A: Voltage responses of a burst-spiking subicular neuron upon depolarizing and hyperpolarizing current pulses. B: Voltage responses of a regular-spiking subicular neuron to depolarizing and hyperpolarizing current pulse. C: The 5-HT4 receptor agonist RS 67333 does not modulate EPSP responses during 30 minutes of wash-in. D: The 5-HT4 receptor antagonist RS 39604 does not alter EPSP responses during 30 minutes of wash-in. Scale bars: 20 mV and 50 ms (B); 2 mV and 20 ms (C1, D1).</p

Effect of 5-HT4 receptors on LTP.

<p>A1: HFS induces LTP under control conditions. A2: The 5-HT4 receptor agonist RS 67333 does not alter LTP. A3: The 5-HT4 receptor antagonists RS 39604 does not modulate LTP. B1: stHFS induces PTP but not LTP under control conditions. B2: The 5-HT4 receptor agonist RS 67333 failed to prime LTP after stHFS. B3: The 5-HT4 receptor antagonist RS 39604 failed to facilitate the induction of LTP after stHFS. Scale bars: 2 mV and 20 ms.</p

Long-term changes in the CA3 associative network of fear-conditioned mice

<div><p></p><p>The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave–ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes.</p></div

Long-term changes in the CA3 associative network of fear-conditioned mice

<div><p></p><p>The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave–ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes.</p></div