Interneuron Diversity series: Interneuron research – challenges and strategies David D. Mott and Raymond Dingledine Department of Pharmacology Emory University School of Medicine Atlanta, GA 30322, USA The field of interneuron research has come of age. An influx of new data has shed light on many areas, but has also highlighted major challenges. The articles in this review series will address several of these chal- lenges, including developing a standardized classifi- cation scheme, defining how the integrative properties of interneurons shape their functional roles (including the generation of oscillatory activity), and identifying molecular mechanisms of synaptic plasticity. New tech- nologies can help us address these problems in ways not previously possible. To coordinate the vast amount of data being generated, we propose the creation of a world-wide-web Interneuron Database that will facili- tate inter-laboratory comparisons and collaborative studies. A well-crafted database has the potential to bring new insight by standardizing and organizing data collected in physiological, anatomical and molecular studies. The interneuron field is no longer a ‘bright young thing’ eagerly courted by granting agencies and journal editors. Instead, it is maturing into a more classic figure as a wider variety of genetic and imaging technologies are brought to bear on the issues of form and function. Since 1995, the interneuron field has been growing more than three times as fast as the whole field of biomedical research, as judged by the number of interneuron-related papers appearing in MEDLINE (http://medline.cos.com/) (bars in Fig. 1) compared with the growth of MEDLINE itself (solid line in Fig. 1). What are these cells? An interneuron is commonly thought of as a neuron that does not project outside the brain region in which its cell body is located – that is, a so-called ‘local circuit neuron’ – a definition a bit fuzzy at the edges but still useful. Not all interneurons are inhibitory (witness the excitatory cholinergic interneurons of the striatum), nor are all inhibitory neurons inter- neurons (e.g. dopaminergic projection neurons in the substantia nigra); finally, not all inhibitory interneurons are GABAergic (e.g. the glycinergic Renshaw cell of the spinal ventral horn). However, this series of reviews will focus mainly on GABAergic inhibitory interneurons of the cortex and hippocampus. Some of the first electrophysio- logical recordings from interneurons were made by Renshaw [1] in the spinal cord, and later by Andersen et al. [2] in the hippocampus. Development of the ability to make whole-cell patch recordings from identified neurons under visual control [3] provided a quantum advance that greatly opened the study of those neurons residing outside the main cell laminae of the brain. The purpose of this article is to lay the groundwork for the series of reviews that follows. These reviews address many different aspects of interneuron research; however, broadly speaking, they can be divided into four central topics: developing a standardized classification scheme for interneurons, defining how the integrative properties of interneurons shape their functional roles, understanding how diverse populations of interneurons generate and pace oscillatory activity, and identifying molecular mech- anisms of synaptic plasticity. Addressing each of these issues represents a major challenge for interneuron researchers today. In the sections that follow we discuss these challenges. We also identify what we believe to be an even greater challenge looming on the horizon: to translate the ever-increasing amount of data in this field into a form that allows a more global understanding of their roles in brain function. We propose the creation of a world-wide- web-accessible Interneuron Database. Such a database could foster collaboration and insights not possible today and bring order and consistency to physiological and anatomical studies. Classification schemes A common theme in interneuron research is that the diversity of interneuron ‘types’ is far larger than that of principal neurons in the same brain region, a theme variously presented as a lament or a cheer depending on the views and needs of the author. Multiple interneuron types interact and function within unique circuits that execute complex functions including learning, memory, emotion, motivation, perception and motor behaviors. Identifying the molecular basis of these higher-order functions is a major goal of neuroscience and has provided an especially difficult challenge for those studying interneurons. Current interneuron classification schemes are anec- dotal in the sense that useful facets or elements of classification, and even the vocabulary used to distinguish one subtype from another, have not been agreed upon by Corresponding author: Raymond Dingledine (rdingledine@pharm.emory.edu). Review TRENDS in Neurosciences Vol.26 No.9 September 2003 484 http://tins.trends.com 0166-2236/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00200-5