Synaptic plasticity in local networks of neocortical layer 2/3

Abstract: The neocortex is a hierarchal organ in which information processing takes on place on many levels, from subcellular signalling all the way to neural networks. Neocortical local neuronal networks (microcircuits), composed of interconnected neurons, form elementary information processing units within the cortex. Pyramidal cells, the primary glutamatergic cells in the cortex, receive synaptic input both from within the neocortex and from more distant cortical and sub-cortical regions. The strength of these inputs can be modified on various time scales. The strength of pyramidal-pyramidal (P-P) cell unitary connections can be modified long-term, depending on the timing of action potentials (APs) in the pre- and post-synaptic cells (spike-timing dependent plasticity, STDP). We reported that the learning rule governing STDP modification is regulated by preceding activity in a postsynaptic neuron. Moreover, we have shown that the difference between STDP observed at layer 2/3 (L2/3) P-P cell connections and STDP studied at other excitatory connections in the neocortex is attributed to a fundamental difference in synaptic properties, suggesting that a L2/3 pyramidal cell is able to recognize its presynaptic partner and form physiologically distinct synapses based on the origin of input. Additionally, the time-window for the induction phase of spike timing- dependent long-term potentiation (STD-LTP) and depression (LTD) at L2/3 P-P connections and its dependence on post-synaptic cell spine calcium concentrations was further examined using data-based computational modelling. We have shown that the resulting synaptic gain change depends on a 15 ms window following synaptic activation. Our data suggested a theoretical enzyme-like Ca2+ sensor that could account for the observed synaptic gain changes in L2/3 P-P connections. Synaptic LTP is thought to be a crucial component underlying learning and memory. Neurodegenerative disorders, such as the Alzheimer s disease (AD) are commonly associated with cognitive impairment and memory loss. We reported that STD-LTP induction at excitatory inputs onto L2/3 pyramidal cells in a mouse model of Alzheimer s disease was impaired as early as at 3.5 months of age, at the very onset of AD-like pathology and prior to amyloid plaque formation. STD-LTP was also abolished at L2/3 P-P connections in wild-type brain slices after soluble non-fibrillar Abeta(25-35) application. The underlying mechanism was the selective Abeta-induced reduction of AMPAR-mediated currents. Meanwhile, STD-LTP induction could be rescued by application of AMPAR desensitization antagonist, cyclothiazide. Thus, we have demonstrated a novel target for AD pathology as well as a means of rescuing STDP under AD s neurodegenerative conditions. Synaptic plasticity consists of multiple variations in synaptic gain taking place over different time scales and between different cell types. In another instance, inhibitory connections from FSN interneuron onto the pyramidal cell can undergo short-term changes in synaptic gain following a postsynaptic AP burst. Previous studies suggested that retrograde dendritic release of glutamate regulates such short-term changes. We further clarified the molecular mechanism of retrograde signalling by showing the SAT2-mediated glutamine transport to be is a necessary precursor for retrograde signalling at FSN-pyramidal cell connections, substantiating the role of glutamate as a retrograde messenger at this synapse.