The cellular generation and spatial distribution of gamma frequency (40– 100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long axis of the dentate hilus, but average coherence decreased rapidly in the CA3 and CA1 directions. Analysis of short epochs revealed large fluctuations in coherence values between the dentate and CA1 gamma waves. Current source density analysis revealed large sinks and sources in the dentate gyrus with spatial distribution similar to the dipoles evoked by stimulation of the perforant path. The frequency changes of gamma and theta waves positively correlated (40–100 Hz and 5–10 Hz, respectively). Putative interneurons in the dentate gyrus discharged at gamma frequency and were phase-locked to the ascending part of the gamma waves recorded from the hilus. Following bilateral lesion of the entorhinal cortex the power and frequency of hilar gamma activity significantly decreased or disappeared. Instead, a large amplitude but slower gamma pattern (25–50 Hz) emerged in the CA3-CA1 network. We suggest that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus. We also hypothesize that under physiological conditions the hilar gamma oscillation may be entrained by the entorhinal rhythm and that gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.

Sharp wave bursts, induced by a cooperative discharge of CA3 pyramidal cells, are the most synchronous physiological pattern in the hippocampus. In conjunction with sharp wave bursts, CA1 pyramidal cells display a high-frequency (200 Hz) network oscillation (ripple). In the present study extracellular field and unit activity was recorded simultaneously from 16 closely spaces sites in the awake rat and the intracellular activity of CA1 pyramidal cells during the network oscillation was studied under anesthesia. Current source density analysis of the high-frequency oscillation revealed circumscribed sinks and sources in the vicinity of the pyramidal layer. Single pyramidal cells discharged at a low frequency but were phase locked to the negative peak of the locally derived field oscillation. Approximately 10% of the simultaneously recorded pyramidal cells fired during a given oscillatory event. Putative interneurons increased their discharge rates during the field ripples severalfold and often maintained a 200 Hz frequency during the oscillatory event. Under urethane and ketamine anesthesia the frequency of ripples was slower (100-I 20 Hz) than in the awake rat (160-200 Hz). Halothane anesthesia prevented the occurrence of high-frequency field oscillations in the CA1 region. Both the amplitude (l-4 mV) and phase of the intracellular ripple, but not its frequency, were voltage dependent. The amplitude of intracellular ripple was smallest between-70 and-60 mV. The phase of intracellular oscillation relative to the extracellular ripple reversed when the membrane was hyperpolarized more than-60 mV. A histologically verified CA1 basket cell increased its firing rate during the network oscillation and discharged at the frequency of the extracellular ripple. These findings indicate that the intracellularly re

SUMMARY Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as has been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons and abnormal neuronal network activity. In addition, treatment with the FDA approved drug risperidone, ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.

High-frequency oscillations (100-200 Hz), termed ripples, have been identified in hippocampal (Hip) and entorhinal cortical (EC) areas of rodents and humans. In contrast, higher-frequency oscillations (250-500 Hz), termed fast ripples (FR), have been described in seizure-generating limbic areas of rodents made epileptic by intrahippocampal injection of kainic acid and observed in humans ipsilateral to areas of seizure initiation. However, quantitative studies supporting the existence of two spectrally distinct oscillatory events have not been carried out in humans nor has the preferential appearance of FR within seizure generating areas received statistical evaluation based on analysis of a large sample of oscillatory events. Interictal oscillations within the bandwidth of 80-500 Hz were detected in Hip and EC areas of patients with mesial temporal lobe epilepsy using wideband EEG recorded during non-rapid eye-movement sleep from chronically implanted depth electrodes. Power spectral analysis showed that oscillations detected from Hip and EC areas were composed of two spectrally distinct groups. The lower-frequency ripple group was defined by a frequency of 96 +/- 14 Hz (median +/- width), while the higher-frequency FR group had a frequency of 262 +/- 59 Hz. FR oscillations were significantly shorter in duration compared with ripple oscillations (P < 0.0001). In regard to the occurrence of FR and ripples in epileptic Hip and EC, the mean ratio of the number of FR to ripples generated in areas ipsilateral to seizure onset was significantly higher compared with the mean ratio of FR to ripple generation from contralateral areas (P = 0.008). Furthermore, sites ipsilateral to seizure onset with hippocampal atrophy had significantly higher ratios compared with sites contralateral to both seizure onset and hippocampal atrophy (P = 0.001). These data provide compelling quantitative and statistical evidence for the existence of two spectrally distinct groups of limbic oscillations that have frequency and duration characteristics similar to those previously described in epileptic rat and human Hip and EC. The strong association between FR and regions of seizure initiation supports the view that FR reflects pathological hypersynchronous events crucially associated with seizure genesis.

Summary:Purpose: Properties of oscillations with frequencies >I00 Hz were studied in kainic acid (-)-treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy.Methods: Prolonged in vivo wideband recordings of electrical activity were made in hippocampus and entorhinal cortex (EC) of (a) normal rats, (b) kindled rats, (c) rats having chronic recurrent spontaneous seizures after intrahippocampal KA injections, and (d) patients with epilepsy undergoing depth electrode evaluation in preparation for surgical treatment.Results: Intermittent oscillatory activity ranging from 100 to 200 Hz in frequency and 50-150 ms in duration was recorded in CAI and EC of all three animal groups, and in epileptic human hippocampus and EC. This activity had the same characteristics in all groups, resembled previously observed "ripples" described by Buzsaki et al., and appeared to represent field potentials of inhibitory postsynaptic potentials (IPSPs) on principal cells. Unexpectedly, higher frequency intermittent oscillatory activity ranging from 200 to 500 Hz and 10-100 ms in duration was encountered only in KA-treated rats and patients with epilepsy. These oscillations, termed fast ripples (FRs), were found only adjacent to the epileptogenic lesion in hippocampus, EC, and dentate gyrus, and appeared to represent field potential population spikes. Their local origin was indicated by correspondence with the negative phase of burst discharges of putative pyramidal cells. Conclusions:The persistence of normal-appearing ripples in epileptic brain support the view that inhibitory processes are preserved. FRs appear to be field potentials reflecting hypersynchronous bursting of excitatory neurons and provide an opportunity to study the role of this pathophysiologic phenomenon in epilepsy and seizure initiation. Furthermore, if FR activity is unique to brain areas capable of generating spontaneous seizures, its identification could be a powerful functional indicator of the epileptic region in patients evaluated for surgical treatment. Key Words: Kainic acid-Temporal lobe epilepsy-Ripples-Oscillations.Ripples are 120-200-Hz field oscillations described in hippocampal (1-3) and parahippocampal areas (4) of normal rats. They are produced by inhibitory postsynaptic potentials (IPSPs) occurring during high-frequency bursts of inhibitory interneurons, which converge on principal neurons (1,3), and they reflect a state of network synchronization that predisposes to normal hypersynchronous events found in the rat hippocampus, such as sharp waves (SPWs) (5).Epileptogenesis in human mesial temporal lobe epilepsy and several chronic experimental models, such as those produced by kindling and kainic acid (KA) administration, is associated with neuronal loss and synaptic reorganization in the hippocampus with resultant strengthening of certain interneuronal connections and increased propensity for hypersynchronization (6)(7)(8)(9)(10)(11)(12)(13)(14)(15...