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At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca](o)) and thus may impair neurotransmission. Increases in [Ca](o) activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits nonselective cation channels at the majority of cortical nerve terminals. This pathway may modulate synaptic transmission by attenuating the impact of decreases in [Ca](o) on synaptic transmission. Using patch-clamp recording from isolated cortical terminals, cortical neuronal pairs and isolated neuronal soma we examined the modulation of synaptic transmission by CaSR. EPSCs were increased on average by 88% in reduced affinity CaSR-mutant (CaSR(-/-)) neurons compared with wild-type. Variance-mean analysis indicates that the enhanced synaptic transmission was due largely to an increase in average probability of release (0.27 vs 0.46 for wild-type vs CaSR(-/-) pairs) with little change in quantal size (23 +/- 4 pA vs 22 +/- 4 pA) or number of release sites (11 vs 13). In addition, the CaSR agonist spermidine reduced synaptic transmission and increased paired-pulse depression at physiological [Ca](o). Spermidine did not affect quantal size, consistent with a presynaptic mechanism of action, nor did it affect voltage-activated Ca channel currents. In summary, reduced CaSR function enhanced synaptic transmission and CaSR stimulation had the opposite effect. Thus CaSR provides a mechanism that may compensate for the fall in release probability that accompanies decreases in [Ca](o).

The posterior wall of the central sulcus in forelimb area of SI has been expolred with extracellular micro-electrodes in baboons lightyl anaesthetized with nitrous oxide and sodium thiopentone. 2. The excitatory responses of 130 single units to low intensity electrical stimulation of the deep radial (muscle) and the superficial radial (cutaneous) nerves have been investigated. 3. Units that responded only to muscle nerve stimulation were located in area 3a but overlapped into area 3b. Units that responded only to cutaneous nerve stimulation were found mainly in area 3b but a number occurred in area 3a. Units that responded to both muscle and nerve stimuli (convergent units) were found throughout area 3a and the rostral part of area 3b. 4. Latency analyses of all three response groups revealed a single population of units responding to low threshold muscle nerve stimulation (mean latency 8.5 msec), and both early and late populations responding to low threshold cutaneous nerve stimulation (mean latencies 9.5 and 13.6 msec respectively). A number of the convergent units had very similar latencies for both inputs. 5. Electrical stimulation within area 3a deminstrated a projection from areas 1 and 3b to area 3a; such a pathway may provide a route for excitation of the late skin population which was found mainly in area 3a. 6. In area 3a units commonly responded to light touch, local pressure or deep pressure but only rarely to movement of hairs. A number of the convergent units responded to natural stimulation of cutaneous receptors.

At a famous meeting of the International Medical Congress held in London on August 4, 1881 Goltz of Strassburg (as it was then spelt) confronted Ferrier of London on the subject of the localization of function in the cerebral cortex. In the first part of this paper the events of that meeting are recalled. Goltz was reluctant to accept the idea of localization because of the restitution of function after injury to the cortex, and because of the general rather than specific residual disabilities of his lesioned dogs. On the other hand, Ferrier's monkeys with cortical lesions demonstrated convincingly that local lesions can produce loss of specific functions. One hundred years later a meeting was held in Oxford on the same topic, and the discussions that took place are summarized in the second part of this paper. No-one doubted the doctrine of localization, namely that different parts of the cerebral cortex normally perform different specialized roles. However, there was no unanimity about how to separate or count the number of different parts of the cortex, nor about the nature of the specialized roles of the parts, nor about any common characteristics of the functions of different parts. In other words, though localization was agreed upon, precisely what the functions are that are localized remained obscure. The third section of this paper advances some speculations on this point. Is a theory of cortical function that would encompass the diverse roles of different parts perhaps within sight, which might even explain the plasticity that must underlie the restitution of function that so impressed Goltz one hundred years ago?

1. Much current thinking about voluntary movement assumes that the segmental gamma loops can function as a servomechanism operated by the brain. However, the alpha motoneurones of the baboon's hand receive a powerful monosynaptic (CM) projection from the precentral gyrus. If servo-driving from the same cortical area is to be possible, it must project independently to the fusimotor neurones and have sufficient power to increase the afferent signalling from the muscle spindles. The cortical thresholds for contraction of m. extensor digitorum communis and for acceleration of the discharges of its muscle spindles have therefore been compared.2. Significant results in this context require that the spindles studied be coupled in parallel with the responding extrafusal muscle fibres. Many spindles were not unloaded by the submaximal contractions evoked by cortical stimulation, although all so tested were unloaded by maximal motor nerve twitches. Reasons are given for thinking that such apparent lack of parallel coupling is an artifact of complex intramuscular anatomy and limitation of shortening by ;isometric' myography.3. A brief burst of corticospinal volleys at 500/sec, which is specially effective in exciting alpha motoneurones over the CM projection, failed to excite spindle afferents at or below the threshold for a cortical ;twitch'.4. In a few epileptiform discharges, bursts of spindle acceleration occurred independently of the clonic contractions. A relatively direct and independent cortico-fusimotor (CF) projection may therefore exist.5. Prolonged near-threshold stimulation at 50-100/sec, which allows time for temporal summation in the less direct projections (e.g. cortico-interneuronal, cortico-rubro-spinal) and does not cause frequency-potentiation at CM synapses, gives abundant evidence of independent alpha and fusimotor projections, whose actions hardly outlast the stimulation period.6. Although independent CF projections would permit servo-driving in natural movements of the hand (given adequate loop gain), there has been no evidence of servo-driving by cortical stimulation or in the spontaneous contractions of light anaesthesia.7. Independent projections would provide for controlled alphagamma co-excitation in the servo-governing of natural movements (Matthews, 1964).8. Evidence is reviewed that the CM projection itself may be part of an important control loop for voluntary movement in primates. A corollary would be a diminished importance of CF projections for segmental loops and an increased importance for maintaining the spindle input to cortical loops.

1. The precentral and postcentral banks of the Rolandic fissure of the arm area of the baboon's cortex have been probed to their depths with extracellular micro-electrodes under nitrous oxide and oxygen anaesthesia, supplemented by minimal intravenous pentobarbitone or chloralose.2. Afferent volleys were sent in from the deep (motor) radial nerve and the deep palmar (motor) branch of the ulnar nerve. Their entry into the central nervous system was timed at the dorsal root entry zone. The nerves were stimulated in continuity and the effects of stimuli below threshold for the motor axons were investigated.3. Area 3a, in the depths of the postcentral bank, which is cytoarchitectonically transitional between areas 3 and 4, is the receiving area for afferent impulses from muscle.4. Evoked potential waves and unitary discharges began 4 msec, and the majority of units discharged between 5 and 10 msec, after the afferent volley reached the dorsal root entry zone.5. Similar responses were elicited by a brief pull (70 mu in 1 msec) or brief vibration (50 mu at 250-400 Hz) applied to the tendons of m. extensor digitorum communis.6. No potential waves were evoked in area 4, even in the depths adjacent to area 3a, by muscle afferent volleys.