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.
"This is supported by a change in the number of GAD65+ terminals from a decrease 2 h after BLA injection (Berretta et al., 2001) to an increase 96 h later (Berretta et al., 2004), and is consistent with the present observation of the difference in theta generation elicited by brainstem stimulation immediately after the injection and 4 days later. Furthermore, some of the more severe functional consequences were reported to occur 15 days after treatment (Gisabella et al., 2009). The increase in GAD65+ terminals, just as the decrease of PV expression in terminals, may thus represent an adaptive mechanism manifested at this early stage which might become unsustainable or inadequate as the disease progresses (Lewis et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity-theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.
Frontiers in Psychiatry 09/2009; 1:132. DOI:10.3389/fpsyt.2010.00132
[Show abstract][Hide abstract] ABSTRACT: N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators of neuronal functions. Here we show that pharmacological (dizocilpine) or genetic (NR1 hypomorphism) disruption of NMDA receptor signaling reduces levels of a brain-specific miRNA, miR-219, in the prefrontal cortex (PFC) of mice. Consistent with a role for miR-219 in NMDA receptor signaling, we identify calcium/calmodulin-dependent protein kinase II gamma subunit (CaMKIIgamma), a component of the NMDA receptor signaling cascade, as a target of miR-219. In vivo inhibition of miR-219 by specific antimiR in the murine brain significantly modulated behavioral responses associated with disrupted NMDA receptor transmission. Furthermore, pretreatment with the antipsychotic drugs haloperidol and clozapine prevented dizocilpine-induced effects on miR-219. Taken together, these data support an integral role for miR-219 in the expression of behavioral aberrations associated with NMDA receptor hypofunction.
Proceedings of the National Academy of Sciences 03/2009; 106(9):3507-12. DOI:10.1073/pnas.0805854106 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is compelling postmortem evidence that GABA cell dysfunction plays a role in the pathophysiology of schizophrenia (SZ). Based on a unique distribution of postmortem abnormalities in layer II of the anterior cingulate cortex and sectors CA3/2 of the hippocampus, we postulated that afferent fibers from the basolateral amygdala to these sites may contribute to diminished GABAergic modulation in these disorders. To test this hypothesis, picrotoxin (PICRO), a non-competitive antagonist of the GABA-A receptor, is stereotaxically infused the basolateral complex of the amygdala (BLA) to increase the flow of excitatory activity into stratum oriens (SO) of sectors CA3/2 of the hippocampus. This pharmacological manipulation results in a selective reduction of GABAergic interneurons containing parvalbumin, calbindin and calretinin in CA3/2. Using single cell recordings in a hippocampal slide preparation, these changes in PICRO-treated rats seem to be associated with a reduction in evoked and spontaneous inhibitory post-synaptic potentials (sIPSCs) recorded from pyramidal neurons in sector CA3/2, but not CA1. A lower resting membrane potential and an increased action potential firing rate have been recorded in interneurons in the SO of CA2/3, but not CA1. Additionally, currents associated with hyperpolarization-activated cationic channels (Ih), which help to control neuronal firing rates of GABA cells in the hippocampus, were also increased. Overall, these studies support the view that postmortem studies contribute information for the development of empiric models of SZ, ones that can be used as translational tools for elucidating the functional changes that may be present in GABA cell subtypes their molecular regulatory mechanisms in this disorder.
Behavioural brain research 07/2009; 204(2):363-8. DOI:10.1016/j.bbr.2009.06.019 · 3.03 Impact Factor
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