Mechanisms underlying diverse short-term plasticity of thalamocortical synaptic responses in the whisker system

• Autores: Giovanni Ferrati
• Directores de la Tesis: Miguel Maravall Rodriguez (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2015
• Idioma: español
• Tribunal Calificador de la Tesis: Emilio Carlos Geijo Barrientos (presid.), Santiago Canals Gamoneda (secret.), Juan Reyes Aguilar Lepe (voc.), Wesseling John (voc.), Jaime de la Rocha Vázquez (voc.)
• Enlaces
  • Tesis en acceso abierto en: RediUMH (pdf)
• Resumen

  • Mechanisms underlying diverse short-term plasticity of thalamocortical synaptic responses in the whisker system In the somatosensory system, thalamocortical (TC) projections are responsible for transmitting sensory stimuli to the cortex and are thus crucial to the perception of sensory stimuli (Bruno, Sakmann, 2006). In the rodent neocortex, layer 4 neurons are the main target of lemniscal thalamic drive via monosynaptic connections. Consequently, the modulation of the dynamics of TC connections onto layer 4 plays a fundamental role in the transmission and processing of sensory information from the external environment. Excitatory connections to layer 4 have been historically described as depressing both in vitro (Gil et al., 1997, 1999; Stratford et al., 1996) and in vivo (Chung et al., 2002; Bruno, Sakmann, 2006). Classic studies were designed to evaluate the depressing effect on TC connections of a periodic stimulation starting from rest. However, this paradigm does not reflect the richness of stimuli received at individual synaptic connections under physiological conditions. In living animals, external stimuli arrive to the cortex together with a complex and rich background of spontaneous and evoked activity, which may affect different connections in distinct ways. Therefore, synaptic plasticity should not be described only in terms of periodic stimulation from rest, or according to the average properties of populations of a given type.

    In order to examine short-term plasticity (STP) dynamics of TC synapses, we measured whole-cell responses to stimulation of TC fibers in layer 4 neurons, using a mouse barrel cortex slice preparation. Previous results from our group (Diaz-Quesada, Martini et al., 2014) showed that STP is variable across TC synapses when evaluated with ongoing, naturalistic stimulation. Consistent with classic earlier work TC connections stimulated from rest (silence) with a regular pattern were characterized by depressing behavior. In contrast, a much more diverse synaptic behavior was found across TC connections when recorded during ongoing stimulation. Each connection responded differentially to particular stimulation intervals, enriching the ability of the pathway to convey complex, temporally fluctuating information. In particular, a change from periodic stimulation to an irregular pattern consisting of different interstimulus intervals (ISIs) yet with identical average frequency (4.59 Hz) unveiled synaptic responses that could be dominated either by facilitation or depression.

    In the present work we have tried to find principles governing this diversity of STP in the TC pathway, focusing on two main factors: the mechanisms underlying STP heterogeneity and the possible rules for specificity across synapses connecting to a single specific neuron. Our results suggest that diverse plasticity is not a consequence of a variable amount of inhibition but occurs across the population of monosynaptic excitatory TC connections. We confirmed that NMDA receptor blockade had no effect on the distribution of STP, but extracellular calcium concentration did, supporting a dependence on presynaptic mechanisms. Therefore we aimed our attention at two presynaptic mechanisms that can regulate release probability and consequently short-term plasticity. First, we analyzed adenosine receptors (A1R): recordings in the presence of adenosine and its antagonist DPCPX and 8-CPT evidenced that perturbing the action of A1R modifies the release probability and short-term plasticity of TC synapses. Specifically, applying adenosine increased facilitation while applying DPCPX enhanced depression. However, these manipulations did not eliminate variability across synapses, suggesting that there is underlying variability in the expression of the machinery for calcium entry and neurotransmitter release. We also examined kainate receptors (KARs), which display age-dependent presynaptic expression in TC synapses and may regulate release probability. We explored possible roles for kainate receptors in short-term plasticity by altering KAR expression both pharmacologically and via the use of knockout mice. We found no evidence for a modulatory effect of KARs on TC short-term plasticity. Finally, concerning specificity, we designed a strategy aimed to find a regulation at the cell level. Our experiments provided weak evidence for postsynaptic clustering of STP properties.