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Potential Targets for Circadian Modulation in the Cortex

Stephen R. Williams
MRC Laboratory of Molecular Biology, University of Cambridge , UK

A myriad of potential sites exist for circadian modulation of the function of neocortical circuits. Here we outline two targets derived from our work on the integrative properties of central neurons and the dynamics of neurotransmission in neocortical circuits, that we consider of physiological importance.

  1. Hyperpolarization-activated cyclic nucleotide gated (HCN) channels. HCN channels are unique in that they are co-activated by membrane voltage and intracellular levels of cyclic nucleotides. We outline two major classes of neuronal behavior controlled by HCN channels: i) constitutive action potential firing. Many classes of central neurons including neurons of the suprachiasmatic nucleus fire action potentials in the absence of synaptic input. We have identified the voltage-activated channel types that maintain constitutive action potential firing in cerebellar Purkinje cells, namely persistent sodium (Nap) and hyperpolarization-activated cyclic nucleotide gated (HCN) channels. In contrast to their function in other neurons, we found that down regulation of HCN channels did not alter the frequency of action potential firing, but prevented constitutive action potential firing, so revealing a form of membrane potential bistability in Purkinje neurons maintained by an interplay between HCN and Nap channels. ii) In contrast, we find that HCN channels are not directly involved in the generation of action potential firing in large neocortical pyramidal neurons, but directly control the spread of synaptic potentials from dendritic site of generation to the axon and so have a dramatic influence on the function of this neuronal class. HCN channels are non-uniformly distributed in layer 5 pyramidal neurons, showing a > 60 fold increase in density at distal apical dendritic sites. Physiologically this dendritic polarization was found to control both the mode of synaptic integration and the amplitude of synaptic potentials at the site of action potential initiation. Circadian modulation of HCN channel function or density will, therefore have a major impact on the operations of these neuronal types.
  2. Use-dependent dynamics of synaptic transmission. The operation of the neocortical microcircuit is dictated by the use-dependent nature of excitatory and inhibitory synaptic transmission. For example, use-dependent synaptic depression has been suggested to allow the dynamic adjustment of intra-cortical excitatory synaptic efficacy according to the rate of presynaptic action potential firing, functioning as a form of gain control that prevents saturation during high frequency activation. Recently we have found that the use-dependent dynamics of excitatory transmission are pathway specific in intra-cortical circuits, by recording unitary EPSPs from layer 5 pyramidal neurons evoked in response to action potential trains in presynaptic layer 2/3 or layer 5 pyramidal neurons. We find that modulation of the probability of neurotransmitter release has a major impact on the ability of synapses to convey physiologically relevant trains of action potentials. Circadian modulation of neurotransmitter systems that target or the direct modulation of the neurotransmitter release machinery will have a substantial impact on the passage of information from one cell to the next in the cortical microcircuit and so the function of the neocortex.