Caffeine is believed to act by blocking adenosine A1 and A2A receptors (A1R, A2AR), indicating that some A1 receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A1R (A1R ؊/؊ ). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A1R ؉/؉ mice, but A1R ؊/؊ mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A1R ؊/؊ mice. In A1R ؉/؊ mice the potency of adenosine was halved, as was the number of A1R. In A 1R؊/؊ mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A1Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important. A denosine acts on four cloned and pharmacologically characterized receptors, A 1 , A 2A , A 2B , and A 3 (1). Adenosine is believed to play a particularly important role in hypoxia and ischemia, and there is evidence that adenosine serves to limit damage secondary to ATP loss (2, 3). However, adenosine may have important actions under more normal physiological circumstances as well. For instance, the effects of caffeine, at concentrations reached during habitual caffeine consumption, are believed to be a consequence of blockade of tonic activity at some A 1 and A 2A receptors (A 1 R and A 2A R) (4). Studies on mice lacking A 2A Rs show that adenosine tonically activates A 2A Rs and that this activation has functional effects, particularly on behavior, blood pressure, and blood platelets (5). A 1 Rs are more widely distributed than A 2A Rs (4, 6), but despite extensive pharmacological studies their physiological and pathophysiological roles remain unclear. Here we show that A 1 Rs mediate physiological as well as pathophysiological effects of endogenous adenosine. In particular, adenosine acts tonically to activate presynaptic and postsynaptic A 1 Rs to depress synaptic transmission and to reduce nociceptive signaling. At elevated levels seen during hypoxia, adenosine acting at A 1 Rs is responsible for the depression of neuronal activity, and in this situation elimination of A 1 Rs results in impaired functional recovery. Materials and MethodsGeneration of A1R Knockout Mice. A major part of the proteincoding sequence of the mouse A 1 R gene (7) corresponding to exon 6 of the human A 1 R gene described by Ren and Stiles (8) was cloned. The targeting construct was b...

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

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How grafted neural stem cells (NSCs) and their progeny integrate into recipient brain tissue and functionally interact with host cells is as yet unanswered. We report that, in organotypic slice cultures analyzed by ratiometric time-lapse calcium imaging, current-clamp recordings, and dye-coupling methods, an early and essential way in which grafted murine or human NSCs integrate functionally into host neural circuitry and affect host cells is via gap-junctional coupling, even before electrophysiologically mature neuronal differentiation. The gap junctions, which are established rapidly, permit exogenous NSCs to influence directly host network activity, including synchronized calcium transients with host cells in fluctuating networks. The exogenous NSCs also protect host neurons from death and reduce such signs of secondary injury as reactive astrogliosis. To determine whether gap junctions between NSCs and host cells may also mediate neuroprotection in vivo, we examined NSC transplantation in two murine models characterized by degeneration of the same cell type (Purkinje neurons) from different etiologies, namely, the nervous and SCA1 mutants. In both, gap junctions (containing connexin 43) formed between NSCs and host cells at risk, and were associated with rescue of neurons and behavior (when implantation was performed before overt neuron loss). Both in vitro and in vivo beneficial NSC effects were abrogated when gap junction formation or function was suppressed by pharmacologic and/or RNA-inhibition strategies, supporting the pivotal mediation by gap-junctional coupling of some modulatory, homeostatic, and protective actions on host systems as well as establishing a template for the subsequent development of electrochemical synaptic intercellular communication.