Amygdala-Dependent Regulation of Electrical Properties of Hippocampal Interneurons in a Model of Schizophrenia
ABSTRACT Schizophrenia (SZ) involves dysfunction of gamma-aminobutyric acid (GABA)ergic transmission in the hippocampus (HIPP), particularly in sector CA2/3. Previous work using a rodent model of postmortem abnormalities in SZ demonstrated that activation of the basolateral amygdala (BLA) results in decreases of GABA currents in pyramidal neurons of CA2/3 but not CA1. In addition, a decrease of GABA cells has been reported in postmortem studies of the HIPP in SZ. In the present work we tested the hypothesis that BLA activation in this rodent model of SZ leads to changes in the electrical properties of interneurons located in sector CA2/3.
Patch clamp recordings in HIPP slices were performed in rat HIPP slices after 15 days of infusion of picrotoxin into the BLA. The intrinsic and firing properties and hyperpolarization-activated currents (Ih) of interneurons were measured in stratum oriens (SO) of CA2/3 and CA1.
The BLA activation was associated with a lower resting membrane potential and an increased action potential firing rate in interneurons of CA2/3 but not CA1. Recordings from interneurons further demonstrated an increase of currents associated with hyperpolarization-activated cationic channels (Ih), which help to control neuronal firing rates and oscillatory rhythms.
Taken together, these results suggest that the enhanced BLA activity is capable of increasing the excitability of interneurons in SO of CA2/3 and might contribute to GABAergic dysfunction in SZ.
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ABSTRACT: Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus. Copyright © 2015 Elsevier B.V. All rights reserved.Schizophrenia Research 02/2015; DOI:10.1016/j.schres.2015.02.002 · 4.43 Impact Factor
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ABSTRACT: Cessation of drug use often coincides with increased food consumption and weight gain in recovering addicts. However, it is not known whether this phenomenon (particularly the weight gain) is uniquely human, or whether it represents a consequence of drug cessation common across species. To address this issue, rats (n = 10/group) were given systemic injections of D-amphetamine (3 mg/kg) or an equal volume of saline vehicle for 9 consecutive days. Beginning 2 days after the final injection, rats were given free access to a highly palatable food mixture (consisting of sugar and butter) along with their standard chow diet, and food consumption and body weight were measured every 48 h for 30 days. Consistent with clinical observations, amphetamine-treated rats showed a greater increase in body weight over the course of the 30 days relative to vehicle-treated rats. Surprisingly, there was no difference in highly palatable food consumption between amphetamine- and vehicle-treated groups, but the amphetamine-treated group consumed significantly more standard chow than the control group. The finding that a history of chronic amphetamine exposure increases food consumption is consistent with previous work in humans showing that withdrawal from drugs of abuse is associated with overeating and weight gain. The current findings may reflect amphetamine-induced sensitization of mechanisms involved in reward motivation, suggesting that weight gain following drug cessation in humans could be due to similar mechanisms.Appetite 03/2014; 78. DOI:10.1016/j.appet.2014.03.013 · 2.52 Impact Factor
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ABSTRACT: A t(1;11) balanced chromosomal translocation transects the Disc1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated ‘sag’ and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5–25 APs at 50 Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input–output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity.European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12549 · 3.67 Impact Factor