Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity

Coping style and depression influence the healing of diabetic foot ulcers: observational and mechanistic evidence

Aims/hypothesis Experimental evidence suggests that the healing of diabetic foot ulcers is affected by psychosocial factors such as distress. We examined this proposal in a prospective study, in which we considered the role of psychological distress and coping style in the healing of diabetic foot ulcers over a 24 week period. We also explored the role of salivary cortisol and matrix metalloproteinases (MMPs) as potential mechanisms. Methods For this prospective observational study we recruited 93 (68 men; mean age 60 years) patients with neuropathic or neuroischaemic diabetic foot ulcers from specialist podiatry clinics in secondary care. Clinical and demographic determinants of healing, psychological distress, coping, salivary cortisol and both MMP2 and MMP9 were assessed at baseline. Ulcers were assessed at baseline and at 6, 12 and 24 weeks post-baseline. The primary outcome was ulcer status at 24 weeks, i.e. healed vs not healed. Results After controlling for clinical and demographic determinants of healing, ulcer healing at 24 weeks was predicted by confrontation coping, but not by depression or anxiety. Patients with unhealed ulcers exhibited greater confrontation coping (model including depression: OR 0.809, 95% CI 0.704–0.929, p = 0.003; model including anxiety: OR 0.810, 95% CI 0.704–0.930, p = 0.003). However, change in ulcer size over the observation period was associated with depression only (p = 0.04, d = 0.31). Healed ulcers by 24 weeks were also associated with lower evening cortisol, higher precursor MMP2 and a greater cortisol awakening response. Conclusions/interpretation Confrontation coping and depression predict ulcer healing. Our preliminary enquiry into biological mechanisms suggests that cortisol and precursor MMP2 may underlie these relationship