Causal relation between dendritic morphology, voltage gated channel expression and presynaptic release mechanisms ?

Lead Research Organisation: School of Pharmacy
Department Name: Pharmacology


Circuits of hundreds of thousands of nerve cells (neurones) in our brains process information, allowing us to recognise important inputs and to take appropriate action. They allow us to learn about novel experiences, placing these, apparently effortlessly, in the context of wider experience. The necessary temporal framework for these computations is provided by the oscillatory patterns of near synchronous activity in populations of neurones, patterns that can be seen in the EEG (electro-encephalogram).

Whether an individual neurone responds to a complex input pattern is determined by the strength of its excitatory inputs at that moment, its state at that time and importantly, by the inhibition it receives. Some of the highly specialised neurones that provide this inhibition
(interneurones) set the rhythms, others determine whether a particular input pattern is strengthened and able, later, to contribute to a memory of a particular experience. Selective loss of specific interneurone types, or alterations in their function occur in many common disease states. Major efforts are therefore being made to understand how this leads to specific psychological and behavioural abnormalities.

The hippocampus is a brain region intimately involved in recognising where we are in our environment, a role that is dependent upon the coordination of rhythmic activity by inhibitory interneurones. This project focusses on a much neglected region of hippocampus (CA2) with unique pathology in schizophrenia and particularly on the interneurones here which display combinations of characteristics unique to this region. These characteristics imply a specific role in coordinating rhythmic activity. By employing a range of techniques we will reveal the functional, molecular and structural features unique to this region and test its contributions to controlling network activity.

Technical Summary

Hippocampal interneurones can be classified by their gross morphology, targets, neurochemistry, firing patterns etc. This classification is fundamental to understanding the different roles interneurones play and the pathologies that involve changes in distinct sub-populations. In CA1 work from many labs has defined subclasses within which interneurones display similar characteristics. Although the boundaries are not rigid and cells displaying similar morphology, but different neurochemistry or electrophysiology can be found, there is significant clustering of properties. For example, there is a large population of fast spiking, parvalbumin (PV) immuno-positive basket cells which share other characteristics. They have similar dendritic morphologies, with relatively narrow arbours spanning all layers from alveus to stratum lacunosum moleculare (SLM). They receive fast EPSPs (excitatory postsynaptic potentials) from neighbouring pyramids that exhibit paired pulse depression and display no ?sag? in voltage responses to hyperpolarizing current.

In striking contrast, OLM (oriens-lacunosum moleculare) cells which target the distal dendritic tufts of pyramids, are somatostatin and weakly PV immuno-positive, have broad, horizontally oriented dendrites confined to oriens/alveus, receive EPSPs from neighbouring pyramids that facilitate and augment powerfully and display what has come to be considered a unique electrophysiological profile, including a pronounced ?sag? indicative of Ih.

It was, therefore, surprising to find that in CA2, PV-immuno-positive basket cells exhibited an electrophysiological profile virtually indistinguishable from OLM cells including pronounced ?sag?. Ih is of particular interest having been implicated in generation and coordination of theta rhythms across hippocampal subfields and between hippocampus and sub-cortical structures participating in theta. Unlike CA1 baskets, but like OLM cells, CA2 basket and some bistratified cells have very broad dendritic arbours in s. oriens-alveus that span all 3 sub-fields, although their arbours in s. radiatum (SR) and SLM resemble those of CA1 interneurones. Moreover, the EPSPs these cells receive from CA2 pyramids do not display depression, indeed some show modest facilitation.

We will therefore test the hypothesis that the long, horizontally oriented dendrites of CA2 interneurones express HCN subunits and postsynaptic receptors and receive excitatory inputs that are distinct from those of their vertically oriented dendrites in SR and SLM. We will employ dual and triple intracellular recordings to compare inputs to CA2 interneurones from pyramids in CA1, CA2 and CA3, manipulate Ih and postsynaptic receptors pharmacologically, reveal cellular markers and the localization of HCN subunits and postsynaptic receptors in these biocytin-labelled cells using confocal immuno-fluorescence and identify the locations of recorded synapses histologically.
Description Growth in the field of cortical synaptic circuitry
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Description Recognition that CA2 displays distinct features and that its function and pathology are also distinct
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Title Physiology, anatomy and pharmacology of cortical synaptic circuitry 
Description Physiology, anatomy and pharmacology of neocortical and hippocampal synaptic circuitry. A very large number of synaptic connections involving different classes of cortical neurones have been studied in detail. In particular, a detailed study of the cell classes and the circuits to which they belong within the CA2 region of the hippocampus is continuing (Dr A. Mercer, with assistance from histology technicians funded by the MRC). 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Many invitations to collaborate (eg. FACETS, COLAMN), contribute to groups developing data-bases for these types of data (eg. INCF) and to speak at international meetings. Entry in 2014 - An archive of neurones, recorded, dye-filled and reconstructed, is being developed under the auspices of the EU Human Brain Project (HBP). Without extremely large resources, this cannot hope to include all the details for all the cell classes in neocortex and hippocampuos that would be useful to the community, but it is hoped that a useful cut-down version will be possible and used first as the basis for a microcircuit model within HBP. 
Description All the boxes below could be ticked for all the years 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Seminars at conferences and in academic institutions - various locations. Group members presented posters at international meetings each year. Teaching in international summer schools almost every year to 2010. MRC panel member. Consortium member - preparation of EU Flagship application.

Consider the investment by Lord Sainsbury in the brain circuitry field, a field that, to a large extent, began with the work of my group in the 1980's - and without which the field would not have flourished. In addition to this institute, several others are being developed across the world
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012
Description Lay abstracts are on the School's website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Available to prospective undergraduate and postgraduate students, as well as the general public.

None tangible
Year(s) Of Engagement Activity 2009,2010,2011,2012
Description Training, seminars, lab visits 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Web sites, Summer Schools (30 international students per year), Visits from other labs (from 1 and up to 6 months in duration) for training purposes, Seminars

Training of young scientists, Contributions thereby to a large number of research projects
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2015