Amygdalar activation alters the hippocampal GABA system: ?Partial? modelling for postmortem changes in schizophrenia

Abstract

Abnormalities in amygdala and hippocampus have been shown to coexist in schizophrenia (SZ). In the hippocampus, compelling evidence suggests that a disruption of GABA neurotransmission is present mainly in sectors CA4, CA3, and CA2. The amygdala sends important inputs to the hippocampus and is also believed to have a defective GABA system in schizophrenia. To explore the possibility that changes in the hippocampal GABAergic system could be related to an increased inflow of activity originating in the amygdala, a "partial" animal model has been developed. In awake, freely moving, rats a GABA(A) receptor antagonist was infused locally into the basolateral nuclear complex of the amygdala (BLn). Within 2 hours, a decreased density of both the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD(65) and GAD(67)) -immunoreactive (IR) terminals was detected on neuron somata in sectors CA3 and CA2, but not in CA1, CA3, or dentate gyrus. An increase of GAD(67)-IR somata was also found in the dentate gyrus and CA4. In anterograde tracer studies, amygdalo-hippocampal projection fibers were exclusively found in CA3 and CA2, but not CA1. Taken together, these results indicate that activation of amygdalo-hippocampal afferents is associated with the induction of significant changes in the GABA system of the hippocampus, with a subregional distribution that is remarkably similar to that found in SZ. Under pathologic conditions, an excessive discharge of excitatory activity emanating from the amygdala could be capable of altering inhibitory modulation along the trisynaptic pathway. This mechanism may potentially contribute to disturbances of GABAergic function in the major psychoses. Such "partial" rodent modelling provides an important strategy for deciphering the effect of altered cortico-limbic circuits in SZ.

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

“…Therefore, a failure of the mPFC to regulate stress in the MAM-treated rat or in the prodromal stage of schizophrenia could contribute to pathological changes in the hippocampus observed in this disorder. It has been shown that activation of the amygdala, which occurs during stress, will lead to parvalbumin interneuron loss in the hippocampus (Berretta et al, 2001) and loss of hippocampal parvalbumin interneurons is proposed to lead to the DA hyper-responsivity in the MAM model (Lodge and Grace, 2007). Thus, a hypersensitivity to stress potentially secondary to decreased mPFC function could initiate a cascade of events during juvenile/adolescent stages to lead to hippocampal dysfunction and the emergence of the schizophrenia-like phenotype observed in the MAM model (Grace, 2004;Thompson et al, 2004).…”

Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment

“…Interestingly, cortex and hippocampus are regions strongly implicated in the pathophysiology of schizophrenia. [35][36][37][38] It was previously reported that density of neurons can be significantly reduced in certain layers of the cortex of schizophrenics. For example, schizophrenic subjects showed a significant decrease in density of nonpyramidal neurons in layer II and pyramidal neurons in layer IV of the anterior cingulated cortex.…”

Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection

“…In contrast, the burst-spiking horizontal and bitufted cells of layers I and II receive on their dendrites both excitatory axon terminal projections from thalamus and cortico-cortical pyramidal neurons 53 and massive excitatory axon terminal projections from the basolateral nucleus of the amygdala. [58][59][60][61] It has been suggested that amygdalo-cortical or cortico-cortical excitatory inputs to layer I and II cortical GABAergic interneurons may help to suppress information arriving at distal pyramidal neuron dendrites and den-dritic spines directly from MD afferent synapses. 52,53 Therefore, as proposed by Benes,58 and based on the data reported in this study, one can hypothesize that the selective decrease in GABAergic inhibitory function observed in layer I of SZP PFC may be the consequence of a specific disorganization of the complex neuronal afferent network reaching GABAergic interneurons of layers I and II from the amygdala or other cortico-limbic regions.…”

“…52,53 Therefore, as proposed by Benes,58 and based on the data reported in this study, one can hypothesize that the selective decrease in GABAergic inhibitory function observed in layer I of SZP PFC may be the consequence of a specific disorganization of the complex neuronal afferent network reaching GABAergic interneurons of layers I and II from the amygdala or other cortico-limbic regions. [58][59][60][61] In schizophrenia, the disorganization of the MD afferent network reaching the GABAergic interneurons of the deeper cortical layers may be less pronounced or localized to only a small subset of neurons such as the chandelier neurons, which have been shown to be dysfunctional in SZP. 23 Is DNMT1 overexpression in layer I cortical GABAergic neurons causally related to the decrease of GAD 67 and reelin?…”