Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice

Abstract

Heterozygous reeler mice (HRM), haploinsufficient for reelin, have been proposed to be a genetic mouse model of schizophrenia. Beside behavioural similarities, HRM also demonstrate several neuroanatomical traits similar to patients suffering from schizophrenia. In the present study using immunocytochemical procedures, we investigated HRM and wild-type mice (WT) for differences in the numbers and densities of glutamic acid decarboxylase (GAD)67 and parvalbumin (PARV)-immunoreactive (IR) neurons in the hippocampus, tyrosine hydroxylase (TH)-IR neurons in the ventral tegmental area (VTA) and substantia nigra (SN), and serotonin transporter (5-HT-T)-IR neurons of the raphe nuclei. We found that HRM, compared with WT, show a significant decrease of GAD67-IR neurons in hippocampal subregion CA1 [stratum pyramidale (SP)], CA2 [stratum oriens (SO), stratum pyramidale (SP) and stratum radiatum (SR)] and dentate gyrus [granule cell layer (GL)], and also a significant decrease of PARV-containing neurons in CA1 (SO, SP) and CA2 (SP). No morphological differences were found in the SN/VTA or raphe nuclei. In conclusion, these results support a hippocampal γ-aminobutyric acid (GABA)ergic dysfunction in HRM as previously described by other authors, and may be based on a downregulation of GAD67 and PARV expressions. In summary, the reelin haploinsufficient mouse may provide a useful model for studying the interaction between reelin and hippocampal GABAergic system, its effect on dendritic spine maturation and plasticity related to schizophrenia.

Distribution of interneurons in the CA2 region of the rat hippocampus

“…In human epileptic tissues, the lack of PV-immunopositivity in CA2 interneurons and a change in the expression of GABA A receptor subunits appear to be responsible for the re-organization of connections in this region (Loup et al, 2000; Andrioli et al, 2007; Wittner et al, 2009). Similarly, a decrease in the number of CA2 interneurons, particularly PV-positive interneurons, has been associated with schizophrenia (Benes et al, 1998; Zhang and Reynolds, 2002; Nullmeier et al, 2011). Although some CA2 interneurons have been described in detail (Mercer et al, 2007, 2012a,b), very little is known about the different cell types in this region.…”

Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice

“…Reelin plays a central role in brain development and synaptic plasticity, making it a highly suitable candidate gene in schizophrenia as reelin mRNA and protein levels are reduced in prefrontal cortex and hippocampus of schizophrenia subjects [22][23][24][25][26]. Interestingly, prenatal hypoxia (PHX) has been shown to decrease reelin protein expression in the hippocampus of adult offspring mice [27], suggesting a potential role of reelin in PHX-induced changes in neuroplasticity.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…It is expressed by GABAergic interneurons and the expression of the GAD1 and RELN genes is tightly coordinated by a common epigenetic mechanism (Costa et al, 2004;Grayson et al, 2005Grayson et al, , 2006Guidotti et al, 2000a;Impagnatiello et al, 1998;Kundakovic et al, 2009;Maloku et al, 2010;Noh et al, 2005;Pesold et al, 1999;Rodriguez et al, 2002;Ruzicka et al, 2007;Tochigi et al, 2008;Veldic et al, 2004Veldic et al, , 2007. In addition, rodent models show that RELN deficiency alone can result in downstream reductions of both GAD1 (Kutiyanawalla et al, 2012;Nullmeier et al, 2011;Pascual et al, 2004;Takayama, 1994) and BDNF (Pillai and Mahadik, 2008). Thus, it appears that RELN and GABAergic deficits in schizophrenia are tightly linked.…”