Change in psychosocial functioning and depressive symptoms during acute-phase cognitive therapy for depression.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent, is recurrent, and impairs people's work, relationships and leisure. Acute-phase treatments improve psychosocial impairment associated with MDD, but how these improvements occur is unclear. In this study, we tested the hypotheses that reductions in depressive symptoms exceed, precede and predict improvements in psychosocial functioning. METHOD: Patients with recurrent MDD (n=523; 68% women, 81% Caucasian, mean age 42 years) received acute-phase cognitive therapy (CT). We measured functioning and symptom severity with the Social Adjustment Scale - Self-Report (SAS-SR), Range of Impaired Functioning Tool (RIFT), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAMD) and Inventory for Depressive Symptomatology - Self-Report (IDS-SR). We tested cross-lagged correlations between functioning and symptoms measured at baseline and the beginning, middle and end of acute-phase CT. RESULTS: Pre- to post-treatment improvement in psychosocial functioning and depressive symptoms was large and intercorrelated. Depressive symptoms improved more and sooner than did psychosocial functioning. However, among four assessments across the course of treatment, improvements in functioning more strongly predicted later improvement in symptoms than vice versa. CONCLUSIONS: Improvements in psychosocial functioning and depressive symptoms correlate substantially during acute-phase CT, and improvements in functioning may play a role in subsequent symptom reduction during acute-phase CT.

Activity-induced large amplitude postsynaptic mPSPs at soma-soma synapses between Lymnaea neurons.

Spontaneous transmitter release has been observed at various synapses that permit analysis at a sufficient resolution as a miniature postsynaptic potential (mPSP). However, the precise mechanisms that regulate spontaneous transmitter release have not yet been fully defined. Activity and ligand-mediated modulation of large amplitude, spontaneous events significantly enhances postsynaptic excitation in the absence of action potential activity suggesting a more complicated role for this mode of transmitter release, and thus warrants further analysis. Here, we used Lymnaea soma-soma synaptic connections to demonstrate that a transient increase in both the frequency and amplitude of spontaneous events (mPSPs) occurs following a short burst of action potentials in the presynaptic cell. These events were of presynaptic origin and the increase in mPSP amplitude could also be achieved with a stimulatory concentration of ryanodine. Ryanodine also occluded the activity-induced increase in mPSP amplitude implicating calcium release from these channels in the production of large amplitude spontaneous transmitter release events. This suggests that presynaptic activity triggers ryanodine receptor-mediated large amplitude minis, indicating that although these events are action potential-independent, they are nevertheless responsive to the prior activity of the synapse.

An action potential-induced and ryanodine sensitive calcium transient dynamically regulates transmitter release at synapses between Lymnaea neurons.

The notion that calcium released through ryanodine receptors effects presynaptic neurotransmitter release is gaining acceptance with the observation that this calcium does indeed contribute to both action potential-evoked and spontaneous transmitter release in a variety of preparations. However, the dynamics of this calcium release and its impact on transmitter release has not yet been fully elucidated. Moreover, in contrast to vertebrate synapses, much less is known about the involvement of ryanodine receptors in the regulation of transmitter release at invertebrate synapses. In this study, we reconstructed specific synapses between individually identifiable preand postsynaptic neurons from Lymnaea to demonstrate that although ryanodine reduces the amplitude of the action potential-induced calcium transient, it does not however, alter the resting calcium level. These data suggest that action potential-induced calcium release through ryanodine receptors is fast and highly dynamic and in turn regulates transmitter release at reconstructed synapses between Lymnaea neurons. This study thus provides direct evidence that a dynamic ryanodine receptor-mediated calcium transient occurs with the presynaptic action potential.

Serotonin modulates transmitter release at central Lymnaea synapses through a G-protein-coupled and cAMP-mediated pathway.

Neuromodulation is central to all nervous system function, although the precise mechanisms by which neurotransmitters affect synaptic efficacy between central neurons remain to be fully elucidated. In this study, we examined the neuromodulatory action of serotonin [5-hydroxytryptamine (5-HT)] at central synapses between identified neurons from the pond snail Lymnaea stagnalis. Using whole-cell voltage-clamp and sharp electrode recording, we show that 5-HT strongly depresses synaptic strength between cultured, cholinergic neuron visceral dorsal 4 (VD4 - presynaptic) and its serotonergic target left pedal dorsal 1 (LPeD1 - postsynaptic). This inhibition was accompanied by a reduction in synaptic depression, but had no effect on postsynaptic input resistance, indicating a presynaptic origin. In addition, serotonin inhibited the presynaptic calcium current (I(Ca)) on a similar time course as the change in synaptic transmission. Introduction of a non-condensable GDP analog, GDP-beta-S, through the presynaptic pipette inhibited the serotonin-mediated effect on I(Ca.) Similar results were obtained with a membrane-impermeable inactive cAMP analog, 8OH-cAMP. Furthermore, stimulation of the serotonergic postsynaptic cell also inhibited presynaptic currents, indicating the presence of a negative feedback loop between LPeD1 and VD4. Taken together, this study provides direct evidence for a negative feedback mechanism, whereby the activity of a presynaptic respiratory central pattern-generating neuron is regulated by its postsynaptic target cell. We demonstrate that either serotonin or LPeD1 activity-induced depression of presynaptic transmitter release from VD4 involves voltage-gated calcium channels and is mediated through a G-protein-coupled and cAMP-mediated system.