Art - Tepper (B)

467 The neostriatum is critically involved in the control and execution of voluntary behavior. Malfunctions of this system underlie several neurological and psychiatric disorders, including Parkinson’s disease and Huntington’s disease. Understanding information processing in the neostriatum requires elucidation of the processes that control the spatiotemporal pattern of activity of its GABAergic spiny projection neurons, which in rodents make up 90–95% of the neuronal population1,2. Neostriatal spiny projection neurons and the diverse classes of interneurons are interconnected in highly organized synaptic microcircuitry and communicate using numerous neurotransmitters and neuromodulators1,2. Despite the importance of this circuitry, the electrophysiological operation of the neostriatum has so far been understood mostly in terms of the interaction between membrane currents of individual spiny projection neurons and their excitatory corticostriatal input2–5. In contrast, very little is known about the nature and function of intercellular interactions and in particular of fast synaptic signaling among striatal neurons. GABAergic afferents are major inputs to spiny projection neurons6–9 and primary determinants of their activity, as a local pharmacological blockade of GABAA receptors in vivo increases the firing rate of these cells by more than 300% (ref. 10). Furthermore, these inhibitory inputs are behaviorally significant because blockade of GABAergic transmission in the neostriatum results in significant activation and/or disruption of motor behavior11,12. Therefore, GABAergic control of spiny projection neurons may be one of the most powerful determinants of the output of the neostriatum, but its functioning is poorly understood. This is primarily because the identity and physiological properties of the functional afferent sources of GABAergic inputs to spiny projection neurons are not known. Thus we cannot determine the temporal and spatial variability of this input and its dynamic or behavioral contingencies. Largely on the basis of anatomical data13, GABAergic inhibition of spiny projection neurons traditionally has been attributed to lateral inhibition among these cells via their local axon collaterals. Tests of this hypothesis have failed to demonstrate any evidence for lateral inhibition (C.J. Wilson, H. Kita & Y. Kawaguchi, Soc. Neurosci. Abstr. 15, 360.1, 1989), and a recent dual recording study14 has provided compelling evidence that this form of interaction is weak or absent in the neostriatum. These findings led to the alternative hypothesis that certain GABAergic aspiny interneurons, which make up only 3–5% of the neurons in the rodent neostriatum, provide the bulk of the inhibitory control of spiny projection cells14,15 (C.J. Wilson, H. Kita & Y. Kawaguchi, Soc. Neurosci. Abstr. 15, 360.1, 1989). We examined the synaptic responses of spiny projection neurons to spiking in GABAergic interneurons to test their possible contribution to the strong inhibitory control of the output of the striatum observed in vivo. To this end, we adapted recently developed techniques of visualized whole-cell recording16–18 to simultaneously record pairs of identified interneurons and projection cells in a mature slice preparation.