Toward a unified hypothesis of interneuronal modulation

It is an apt oversimplification to state that the brain contains two functionally defined types of neurones, the principal neurones and the interneurones. In this abridged neuro-mology the principal neurones carry information from place to place, while interneurones act locally to shape that information once it arrives at its destination. Interneurones do the pacing, the timing and the synchronizing of many neural circuits. They curtail and allow information passage through neural circuits. They do this in both spacial and temporal domains. Because of their central role, those influences that control and/or modulate interneuronal function will be among the most important to understand. The study of interneuronal function has proceeded for the past three decades along two broad frontiers: the classification of the basic properties (anatomical, neurochemical and electrophysiological) of these neurones and the modulation of their activity by neurotransmitters and other substances. Both of these lines of enquiry have had as an underlying goal understanding the rules that govern the influence of interneurones over neural circuitry (Maccaferri & Lacaille, 2003). Within this quest, the grail (perhaps not holy, but at least very nice!) has been a hypothetical construct that would unify the anatomical, chemical and physiological properties with modulatory findings. One of the most potent modulatory substances acting on interneurones is acetylcholine, working through muscarinic receptors. Data that had been collected so far has seemed to suggest that with regard to muscarinic action, there was at best, a weak relationship between morphology and modulation. (Parra et al. 1998; McQuiston & Madison, 1999a). With the publication of an article in this issue of The Journal of Physiology, Lawrence et al. (2006) have taken a large step forward in unifying these two threads of investigation. By confining their analysis to a larger number of interneurones within one layer of CA1 hippocampus (stratum (s) oriens), they have found a stronger correlation between structure and function than was previously appreciated. For the purposes of this study, interneurones of the hippocampal stratum oriens were divided into two anatomical subtypes, the so-called O-LM (oriens–lacanosum/moleculare) interneurones and non-O-LM s. oriens interneurones. O-LM neurones gained their name from their anatomical morphology. Their soma is found exclusively in the s. oriens (O), but their axonal projection travels to and ramifies primarily in the s. lacanosum moleculare (LM). From their anatomical shape, it has been deduced that this type of interneurone serves the function of ‘listening’ to input from contralateral hippocampus, and then inhibiting ipsilateral perforant path input to the principal pyramidal cells. Thus, they would serve as a filter to sharpen information lateralization. The non-O-LM cells, on the other hand, comprise several anatomical subtypes, suggestive of different roles. More specifically, Lawrence et al. (2006) have shown that O-LM interneurones are made more excitable by muscarinic receptor activation. In addition, a large after-depolarizing potential (ADP) is evoked by muscarinic receptor activation via the blockade of an M-current, a calcium-activated potassium current and a non-selective cation current (e.g. Fig. 1). This latter effect is mediated by M1 and/or M3 muscarinic receptor subtypes. In contrast, non O-LM interneurones do not tend to display an ADP or a frank depolarization, and tend to either increase or decrease their excitability in the face of muscarinic agonism. While Lawrence et al. confine their analysis to the effects of muscarinic agonism in hippocampal CA1 stratum oriens interneurones, the significance of the study goes beyond just suggesting principles of cholinergic control of GABA release in the hippocampus. It would be fair to say that these results, along with others that are beginning to suggest specific correlation between the basic properties of interneurones and their transmitter/modulator sensitivity (e.g. McQuiston & Madison, 1999b; Klausberger et al. 2003; Pouille & Scanziani, 2004) help a great deal in the march toward a unified hypothesis of interneuronal function, in that they demonstrate that the anatomical configuration, and thus the putative role of an interneurone in the neural circuitry, is correlated with the modulation to which that interneurone is subject. Figure 1 An example of a muscarine-induced afterdepolarizing potential (ADP) that follows a current-induced depolarization in a hippocampal interneurone