Thesis (M.D)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 80-124) Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph.D.)--Duquesne University, 2009. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 123-151) and index.

Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Médicas / Made available in DSpace on 2018-08-06T21:33:07Z (GMT). No. of bitstreams: 1 Coan_AnaCarolina_M.pdf: 12048096 bytes, checksum: d15d096a9718e3a561f6bbab24d2755e (MD5) Previous issue date: 2006 / Resumo: Introdução: Inúmeros fatores influenciam a recidiva de crises epilépticas em pacientes em remissão submetidos à retirada da droga anti-epiléptica (DAE). O tipo de síndrome epiléptica e a pesença de anormalidades estruturais são consideradas variáveis importantes. Porém, nenhum estudo demonstrou a influência de alterações em exames de ressonância magnética (RM) no prognóstico de reciva de crises destes pacientes. Objetivo: Determinar a presença e o grau de atrofia hipocampal (AH) e a presença de hipersinal hipocampal em pacientes há pelo menos dois anos livres de crises, que foram submetidos à retirada da DAE, e correlacionar a AH e a hiperintensidade do sinal hipocampal com a recorrência de crises. Métodos: De um grupo de 99 pacientes com epilepsia parcial acompanhados em um protocolo para retirada da DAE após o controle adequado das crises, foi realizado o estudo volumétrico da estrutura hipocampal nos 84 pacientes que puderam ser submetidos a exame de Ressonância Magnética (RM). Todos os pacientes foram acompanhados por um longo período (5,7 a 11 anos). Os volumes hipocampais (VHc) foram determinados em imagens coronais T1-IR de 3 mm através do software NIH, com correção pelo volume intra-cranial total de cada paciente. A intensidade do sinal hipocampal foi determinada através da relaxometria de T2 duplo-eco (realizada em 57 pacientes) através do software NIH. A AH foi caracterizada tanto pelo VHc como pelo índice de assimetria hipocampal (IAHc, razão do menor lado/maior lado) abaixo de dois desvios-padrão da média do grupo controle. A hiperintensidade de sinal foi determinada pelo prolongamento do tempo de T2 pelo menos dois desvios-padrão acima da média do grupo controle. Resultados: Um total de 50/84 pacientes (59,5%) apresentaram recorrência de crises após a retirada da DAE. A AH esteve presente em 39/84 (46%). A presença de AH se relacionou significativamente a uma maior freqüência de recorrência de crises (29/39; 74%) após a retirada da DAE em comparação com os pacientes sem AH (21/45; 47%) (x2, p=0,01) A análise de sobrevivência (Kaplan-Meier) demonstrou uma diferença significativa de recorrência de crises entre pacientes com ou sem AH (Mantel, p=0,006). A probabilidade estimada de permanecer livre de crises 5 anos após a retirada da DAE foi 62% para aqueles sem AH e aproximadamente 28% para aqueles com AH. Relaxometria de T2 com sinal anormal foi mais freqüente em pacientes com recorrência de crises (10/31; 32%) do que naqueles que permaneceram livres de crise (3/26, 11%), apesar desta diferença não ser significativa, (x2, p=0,1) devido ao tamanho da amostra. No entanto, a análise de sobrevivência (Kaplan-Meier) demonstrou uma diferença significativa de recorrência de crises entre pacientes com ou sem sinal anormal à relaxometria de T2 (Tarone-Ware, p= 0,013). A probabilidade estimada de permanecer livre de crises 5 anos após a retirada da DAE foi 62% para aqueles sem sinal hipocampal anormal e aproximadamente 23% para aqueles com sinal hipocampal anormal à relaxometria de T2. Conclusões: A recorrência de crises após a retirada da DAE foi mais frequente entre os pacientes com AH ou sinal hipocampal anormal. A avaliação de imagens de RM deve ser levada em consideração antes da decisão da retirada da DAE em pacientes com epilepsias parciais / Abstract: Background: Various factors influence the proportion of patients with epilepsy who were previously seizure-free under medication, and will present seizure recurrence after antiepileptic drug (AED) withdrawal. Epilepsy syndrome and presence of structural abnormalities are considered important variables. Objective: To determine the presence and degree of hippocampal atrophy (HA) and hyperintense hippocampal signal in patients who were seizure-free for at least two years and underwent AED withdrawal, and to correlate HA and hyperintense hippocampal signal with seizure recurrence. Methods: From a group of 99 patients with partial epilepsy followed in a protocol for AED withdrawal after seizure control, we performed hippocampal volumetric study in 84 patients with available high resolution MRI All patients were followed up for a long period of time. Hippocampal volumes (HcV) were determined using 3 mm Tl-IR coronal images using NIH software, with correction by the variation of total intracranial volumes. Signal intensity of hippocampal structure was determined by double-echo T2 relaxometry (obtained for 57 patients) using NTH software HA was determined for either HcV or hippocampal asymmetry index (HcAI, smaller/larger ratio) below two standard deviations from the mean of the control group. Signal hyperintensity was determined for prolonged T2 relaxation time above two standard deviations from the mean of control group. Results: A total of 50/84 patients (59.5%) had seizure recurrence after AED withdrawal HA was present in 39/84 (46%). The presence of HA was associated with a significant higher frequency (29/39, 74%) of seizure recurrence after AED withdrawal compared to those without HA (21/45; 47%) (x2, p=0.01). Survival analysis (Kaplan-Meier) demonstrated a significant difference of seizure recurrence between patients with or without HA (Mantel, p= 0 006). The estimated probability of remaining seizure free 5 years after AED withdrawal was 62% for those without HA and approximately 28% for those with HA. Abnormal T2 relaxometry was more frequent in patients with seizure recurrence (10/31; 32%) than in those who remained seizure free (3/26; 11%) although this difference was not significant (x2, p=0.1) due to sample size. Survival analysis (Kaplan-Meier) demonstrated a significant difference of seizure recurrence between patients with or without abnormal T2 relaxometry (Tarone-Ware, p= 0.013) The estimated probability of remaining seizure free at 5 years after AED withdrawal was 62% for those without abnormal hippocampal signal and approximately 23% for those with abnormal hippocampal signal. Conclusions: Seizure recurrence after AED withdrawal was more frequent among patients with HA and abnormal hippocampal T2 signal MRI evaluation should be considered before decision for AED discontinuation in seizure-free patients with partial epilepsies / Mestrado / Neurociencias / Mestre em Fisiopatologia Médica

Orientadores: Li Li Min, Fernando Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T03:09:51Z (GMT). No. of bitstreams: 1 Bonilha_LeonardoFatorGouvea_D.pdf: 8420238 bytes, checksum: 016f0b30e07800517df57c5fc2672c09 (MD5) Previous issue date: 2004 / Resumo: A esclerose hipocampal (EH) é a alteração histológica mais comum em pacientes com epilepsia do lobo temporal medial (ELTM). A Ressonância Magnética (RM) de crânio possibilita a detecção in vivo de sinais associados à EH, permitindo que pacientes com EL TM reftatária à medicação sejam submetidos à ressecção cirúrgica do hipocampo para tratamento de crises epilépticas. As causas de reftatariedade à medicação e ao tratamento cirúrgico ainda são desconhecidas, porém supõe-se que um dos motivos seja a presença de lesão neuronal acometendo outras áreas cerebrais além do hipocampo. O uso da morfometria por RM permite avaliação do dano neuronal tanto no hipocampo como em outras estruturas cerebrais através da avaliação e quantificação da atrofia presente nestas estruturas. Para avaliação pormenorizada das estruturas cerebrais foi realizada a implementação e validação de um protocolo anatômico para mensuração da região mesial do lobo temporal, com uso de RM tridimensional de alta definição. Foi também definido um protocolo para volumetria automatizada baseada em voxel de todo o cérebro. Foi observado que o dano neuronal em pacientes com EL TM se estende além do hipocampo e acomete regiões que se conectam funcionalmente e anatomicamente ao hipocampo. Tál achado sugere que exista lesão abrangendo uma rede neuronal, o que pode ser responsável em conjunto pelas manifestações clínicas observadas nesses pacientes / Abstract: Hippocampal sclerosis (HS) is the most common histological finding in patients with media! temporal lobe epilepsy (MTLE). Magnetic resonance imaging (MRl) permits in vivo detection of signs that are associated to HS, permitting the surgical treatment for these patients. The causes of medical and surgical reftactoriness observed in patients with MTLE are still unknown. One possible explanation is the fact that the neuronalloss encountered in these patients spans over other brain areas beyond the hippocampus. The use of morphometric quantification of brain structures through MRI is a powerful tool to investigate the neuronalloss in the hippocampus and in other areas of the brain. In order to assess the neuronal damage in brain structures of patients with MTLE, we developed a protocol for manual MRI morphometry of the media! temporallobe structures. We also developed an automatic protocol to assess the concentration of gray matter in the whole brain of these patients through the use of Voxel Based Morphometry. We observed that patients with MTLE exhibit neuronal loss that is not restricted to the hippocampus, but affects di:fferent areas throughout the brain that are functionally and anatomica1ly connected to the hippocampus. These findings suggest that a lesion of a network of neural structures may be responsible for the clinical symptomatology exhibited by patients with MTLE / Doutorado / Neurologia / Doutor em Ciências Médicas

Immunocytochemical studies have demonstrated that nerve fibers containing immunoreactive oxytocin and vasopressin project to many areas of the central nervous system, including the hippocampus and the lateral septum (Buijs, 1980; Sofroniew and Weindl, 1978). Biochemical, physiological and behavioral studies of the effects of these peptides on the CNS have indicated that they are involved in functions as diverse as the control of serotonin turnover (Auerbach and Lipton, 1982), the regulation of body temperature (Kasting et. al., 1979) and the retention of conditioned behavior (de Wied et. al., 1974; Koob and Bloom, 1982). The presence of immunoreactive vasopressin (iAVP) in the hippocampus of Wistar rats was confirmed by radioimmunoassay. The vasopressin content of the dorsal hippocampus was 30.3 ± 7.3 pg iAVP/mg soluble protein and that of the ventral hippocampus was 81.4 ± 8.3 pg iAVP/mg soluble protein, while tissue from the cerebral cortex contained no detectable vasopressin. That this immunoreactivity was due to vasopressin was confirmed by the absence of immunoreactivity in hippocampal or cortical tissue from Brattleboro rats, which are genetically unable to synthesize vasopressin. Vasopressin applied by iontophoresis was found to increase the activity of neurones in the lateral septum and in the hippocampus of the anesthetized rat. There was no obvious difference between the response of spontaneously active cells and the response of cells excited by continuous iontophoresis of glutamate or acetylcholine. Repeated application of vasopressin resulted in a decline in the magnitude of the response, but at least part of this decline was due to progressive blockage of the micropipette barrel rather than to tachyphylaxis. Oxytocin, tested only in the septum, was without effect. When applied by superfusion onto rat hippocampal slices, the NHP peptides were found to increase the activity of 88% of spontaneously active cells and to induce activity in many neurones that were not spontaneously active. Arginine vasopressin, lysine vasopressin, arginine vasotocin, and oxytocin were found to be of roughly equivalent potency, producing a dose dependent response in the range 10⁻⁹-10⁻⁶M. Most cells were tested with more than one peptide and were always found to respond either to all or to none of them. There was no decline in responsiveness when cells were subjected to repeated applications of peptide, but continuous application caused the cells to become unresponsive. Following continuous application of oxytocin, a cell failed to respond to both oxytocin and vasopressin, as would be expected if the two peptides were acting on the same receptor. The analogues ddOT, ddAVP, and Gly⁷0T were also active, but the oxytocin fragment PLG had no effect, and the vasopressin fragment DGAVP was extremely weak. The response to the peptides could be blocked by vasopressin antagonists. The peptide sensitive cells appeared to be pyramidal cells rather than interneurones, since the peptide induced activity could be inhibited for about 200-600 msec by electrical stimulation of the stratum radiatum. / Arts, Faculty of / Philosophy, Department of / Graduate

In the hippocampus, tetanic stimulation of an input results in a long lasting potentiation (LLP) of synaptic transmission involving that input. While high frequency tetanic stimulations are preferred to elicit LLP, low frequency tetanus induces homosynaptic and heterosynaptic depressions. The present investigations were conducted to (1) analyse the characteristics of pulses in orthodromic and antidromic tetanic stimulations and relate them to post-tetanic changes in evoked potentials (2) determine if potentiation and depression co-occur and (3) determine whether an established LLP in one input is subsequently modified by the initiation of LLP in another input (to the same CAlb neurons) or whether LLP can be reversed by homosynaptic and heterosynaptic depressions and lastly (4) determine how interference or enhancements of calcium and potassium fluxes with pharmacological substances related to potentiation and depression. Experiments were conducted on transversely sectioned rat hippocampal slices. Evoked potentials in subfield CAlb were elicited with stimulations of CAlb axons, commissural (Com), or Schaffer collaterals (Sch). Sch terminal excitability was tested with a stimulating electrode placed in the Sch/CAlb synaptic regions. Recordings were made with microelectrodes positioned in the CAlb cell bodies and/or dendritic regions, and in field CA3. It was found that potentiation and depressions co-occur. Presynaptic volleys accompanied all tested tetanic trains. Similarly, antidromic trains discharged CAlb neurons continuously but did not cause LLP. Low frequency tetanic trains caused facilitated synchronous discharges of CAlb neurons during significant portions of these trains. In contrast, few if any syn- chronous discharges followed high frequency tetanus. Yet high frequency tetanus elicited LLP and low frequency tetanus caused homo- and heterosynaptic depressions. An established LLP could be masked but not reversed by homo- and heterosynaptic depressions but this LLP was not interrupted by subsequently induced LLP of a separate input. Iontophoretic L-glutamate on CAlb cell bodies caused depression which was more pronounced if a tetanus was evoked during L-glutamate ejections. The depressions to low frequency tetanus and L-glutamate were counteracted by verapamil. Lastly, barium and 4-aminopyridine potentiations were reversed with washing. Applications of these drugs did not alter Sch terminal excitability. Tetanus induced during the presence of 4-aminopyridine still elicited LLP. It is concluded that homo- and heterosynaptic depressions are partly due to the accumulation of calcium into the CAlb neurons. The magnitude of calcium entry into presynaptic and postsynaptic regions is governed by the tetanic frequencies evoked. The results are consistent with a presynaptic mediated LLP. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The electrophysiological properties of dentate granule cells and hippocampal pyramidal neurons were examined with extracellular and intracellular recording techniques in the hippocampal slice. Intracellular analysis revealed that there may exist two populations of granule cells distinguishable by the presence or absence of non-linear current-voltage (I-V) membrane properties (anomalous rectification, AR). The granule cells exhibiting AR also maintained greater resting membrane potentials and action potential (AP) amplitude values. The membrane input resistance (Rn) and time constant (Tc) measurements were similar between the populations in response to hyperpolarizing current injection, but granule cells displaying AR had significantly higher Rn and Tc values in response to depolarizing pulses. Both groups also responded to maintained depolarizing current injection with repetitive AP discharges; however, this response accommodated. Upon termination of the depolarizing current injection, an afterhyperpolarization (AHP) resulted, the amplitude of which appeared to depend on the duration of the depolarizing pulse and not on the number of APs generated during the pulse. Stimulation of either the lateral (LPP) or medial (MPP) perforant paths evoked a monosynaptic EPSP followed by a depolarizing afterpotential (DAP) and a long afterhyperpolarization (LHP). In contrast, antidromic stimulation elicited a depolarizing-IPSP (D-IPSP) and a LHP. Both the DAP and D-IPSP were reversed by membrane depolarization, whereas, the LHP was inverted by membrane hyperpolarization. In all cases, however, the EPSP could not be inverted. Afterpotentials were associated with an increase in conductance, but the change accompanying the LHP was less than the DAP and D-IPSP. In addition, by reducing the [Ca]₀ and increasing the [Mg]₀, the DAP was attenuated and the LHP eliminated. Similar results were also obtained with the GABAB agonist, baclofen. Paired pulse stimulation of either the LPP or MPP resulted in the potentiation of the intracellular EPSP at condition-test (C-T) intervals less than 100 ms; however, simultaneous extracellular records from the granule cell layer (GCL) illustrated depression of the EPSP. The discrepancy between the extra- and intracellular recordings was shown to be related to the presence of the DAP. In addition, the MPP evoked test EPSP at C-T intervals greater than 150 ms exhibited inhibition regardless of whether it was recorded inside or outside the granule cell and this EPSP depression was partially due to the granule cell LHP. The LPP evoked test EPSP potentiated at all C-T intervals less than 1s when recorded from the outer molecular layer (OML) but was inhibited at both the GCL and intracellular recording sites. These data confirmed that postsynaptic processes contribute to the short-term alterations observed with paired pulse stimulation. The typical inhibition-potentiation-inhibition sequence of the perforant path (PP) evoked population spike (PS) was noted at C-T intervals of 20, 80 and 400 ms, respectively. The inhibition of the PS at 20 ms was abolished with perfusion of the GABA antagonist, bicuculline. In contrast, the PS inhibition at 400ms was unaffected by this treatment but was slightly attenuated by the gKca antagonist TEA. A number of factors appeared to contribute to the potentiation of the PS: 1) reduction in AP threshold; 2) the presence of the DAP; and 3) extrasynaptic events. In addition to the PS data from normal tissue, hippocampal slices from chronically kindled rats exhibited depression of the PS at all C-T intervals tested. This augmentation of inhibition was dependent on the presence of hippocampal afterdischarges but not on motor seizures. Perfusing the kindled slices with either bicuculline or lowered [Cl]₀ did not markedly reverse the enhanced inhibition at C-T intervals which displayed dramatic facilitation in normal slices. Intracellular recordings of granule cells obtained from kindled slices also exhibited an increase in the Rn and Tc. Both the alterations in inhibition and membrane characteristics appear to be localized to.the granule cells, since these changes were not observed in CA1 pyramidal neurons. These data indicate that short-term and long-term alterations in granule cell neuronal excitability are partially due to changes in the postsynaptic membrane. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

In the hippocampus, transient tetanic stimulations of inputs, or brief simultaneous pairings of conditioning intracellular postsynaptic depolarizations with activated presynaptic afferents at low stimulation frequencies, result in input specific long-term potentiation (LTP) of synaptic transmission. LTP lasts for hours in vitro, or weeks in vivo, and it is thought to be involved in memory and learning. Experimental evidence in the literature suggests that postsynaptic mechanisms mediate LTP induction, whereas presynaptic mechanisms are involved in its maintenance. Since LTP is thought to be generated by postsynaptic mechanisms and to be subsequently maintained by presynaptic processes, this suggests the presence of feedback interactions during LTP development, however, the experimental evidence for such interactions is presently not available. Consequently, the present studies were conducted to examine possible feedback interactions between postsynaptic and presynaptic elements in the hippocampus. Furthermore, the experiments tested the hypothesis that substances released during tetanic stimulations caused the release of endogenous substances that interacted with activated afferents resulting in alterations in presynaptic functions and LTP production. Experiments were conducted using transversely sectioned guinea pig hippocampal slices. Briefly, physiological medium containing 3.5 mNi Ba++ and 0.5 mM Ca (denoted as Ba medium) was used to induce the asynchronous release of transmitters, observed as evoked miniature EPSPs (minEPSPs) in CA1b neurons after stimulation of the stratum radiatum. During transient Ba++ applications, short bursts of evoked minEPSPs were observed following stimulations of the stratum radiatum or conditioning depolarizing current injections into CA1b neurons. Moreover, the frequencies of minEPSPs were significantly increased immediately after simultaneous stimulations of the stratum radiatum and conditioning depolarizing current injections into CA1b neurons. Significant increases in the frequencies of evoked minEPSPs were also observed during LTP induced by tetanic stimulations. The above increases in the frequencies of evoked minEPSPs were attributed, in part, to presynaptic changes resulting in increases in transmitters released. However, a thorough quanta! analysis is requirea to substantiate this conclusion. In order to determine whether any substances released during tetanic stimulations were involved in the mooulation of presynaptic functions and induction of LTP, samples were collected from guinea pig hippocampus and rabbit neocortex. It was found that samples that were collected during tetanic stimulations of the guinea pig hippocampus in vivo or rabbit neocortex in vivo produced LTP in the guinea pig hippocampal slice in vitro. Applications of these samples after heating and cooling failed to induce LTP. Subsequent studies demonstrated that PC-12 cells incubated in growth medium treated with samples collected during tetanic stimulations of the rabbit neocortex developed extensive neurite growths. In contrast, PC-12 cell cultures incubated in (1) heated and cooled samples, (2) samples collected in the absence of tetanic stimulations of the rabbit neocortex, or (3) plain growth medium, failed to develop neurite growths. In addition, PC-12 cell cultures that were incubatea in growth medium containing samples collected during tetanic stimulations plus saccharin (10 mM), a substance known to inhibit N6F-dependent neurite growth, failed to develop neurites. In separate experiments it was found that saccharin could block (1) the synaptic potentiating effects of the above collected and applied endogenous substances, and (2) LTP induced with tetanic stimulations, in the guinea pig hippocampus in vitro. The concentrations of saccharin used in these studies had insignificant effects on resting membrane potentials, input resistances, spontaneous or evoked responses of CA1b neurons. Furthermore, CA1b neuronal depolarizations induced by N-methyl-DL-aspartate (NMDA) or with tetanic stimulations of the stratum radiatum, were not altered by saccharin applications. In addition, saccharin had insignificant effects on paired-pulse facilitation, post-tetanic potentiations, minEPSP frequencies in CA1b neurons, and Schaffer collaterals terminal excitability. These results suggest that saccharin blocked LTP through mechanisms different from either non-specific alterations in CA1b cell properties or NMDA receptor activation. Perhaps the agent antagonized LTP at a step beyond NMDA receptor activation. That saccharin blocked LTP caused by the applied neocortical sample as well as by tetanic stimulation of the stratum radiatum, and that saccharin also blocked neurite growth in PC-12 cells induced by the neocortical samples, raises the prospect that growth related substances are involved in LTP generation. In other control experiments, it was found that the potentiating effects of the collected endogenous substances were not antagonised by atropine or dihydro-e-erythroidine. Heated and then cooled solutions of glutamate (a putative transmitter at the Schaffer col laterals-CA1b synapses) still maintained their actions on the CA1b population spike. While brief applications of 2.5 μg/ml exogenous NGF (from Vipera lebetina) during low frequency stimulations of the stratum radiatum did not consistently induce LTP, this peptide significantly facilitated the development of LTP when applied in association with tetanic stimulations of weak inputs in the CA1b area. These weak inputs could not support LTP if tetanized in the absence of the exogenous NGF. The results of the studies in this thesis suggested that postsynaptic depolarizations modulated presynaptic functions in the hippocampus. Tetanic stimulations in hippocampus and neocortex caused the release of diffusible substances, which were probably growth related macromolecules, that interacted with activated presynaptic afferents and/or subsynaptic dendritic elements resulting in LTP development. The precise locus of actions of these agents awaits further investigations. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The hippocampus is a brain structure known for its role in declarative memory- our ability to consciously recall facts and events. The hippocampus is a highly heterogeneous brain structure, and the small subregion CA2 has been shown to be necessary for the formation of social memories, the ability of an animal to recognize previously encountered conspecifics. Changes in excitatory/inhibitory balance have been observed in CA2 in humans with schizophrenia and in mouse models of schizophrenia, suggesting that these alterations may lead to some of the social dysfunction seen in schizophrenia. Although the hippocampal CA2 region has been implicated in social memory and neuropsychiatric disorders, little is known about how CA2 neural activity may encode social interactions and how this coding may be altered in disease. To see if and how CA2 codes for social interactions, I recorded extracellularly from CA2 pyramidal neurons as mice engage in a three-chamber social interaction task where the mice interact with the following task dimensions: space, novel objects, familiar social stimuli, novel social stimuli, and the passage of time. I found that whereas CA2 activity fails to provide a stable representation of space, unlike most other dorsal hippocampal subregions, it does code for contextual changes and for novel social stimuli. In Df(16)A+/- mice, which model the 22q11.2 microdeletion, a major schizophrenia risk factor, CA2 activity fails to encode context or social novelty, consistent with the deficit in social memory seen in these mice. In contrast, CA2 activity shows a surprising increase in spatial coding in Df(16)A+/- mice. These mice were previously shown to have a loss of inhibitory neurons within CA2, and a hyperpolarization of the CA2 pyramidal neuron resting potential. This hyperpolarization is likely due to upregulation of the outward rectifying TREK-1 K+ channel. I found that administration of a TREK-1 K+ channel antagonist rescued social memory and restored the normal CA2 coding properties in the mutants. These results demonstrate a crucial role for CA2 in the encoding of social stimuli and the expression of social memory, and suggest that dysfunction in CA2 may underlie deficits in social function seen in some forms of neuropsychiatric disease.