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Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

ABSTRACT: Inhibitory neurotransmission is primarily mediated by ?-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the ?1-6, ?1-3 or ?2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the ?1, ?1 and ?2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of ?1, ?2, ?1, ?2 and ?2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the ?1 and ?2 GABA(A)R subunits and subunit isoforms in schizophrenia. The ?2 subunit is expressed as three isoforms at 52 kDa (?2(52 kDa)), 50 kDa (?2(50 kDa)) and 48 kDa (?2(48 kDa)). In the ER, we found increased total ?2 GABA(A)R subunit (?2(ALL)) expression driven by increased ?2(50 kDa), a decreased ratio of ?(248 kDa):?2(ALL) and an increased ratio of ?2(50 kDa):?2(48 kDa). Decreased ratios of ?1:?2(ALL) and ?1:?2(50 kDa) in both the ER and SYN fractions and an increased ratio of ?2(52 kDa):?(248 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs.

SUBMITTER: Mueller TM

PROVIDER: S-EPMC4564557 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

Mueller T M TM Remedies C E CE Haroutunian V V Meador-Woodruff J H JH

Translational psychiatry 20150804

Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the α1-6, β1-3 or γ2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia ...[more]

PMID: 26241350

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Project description:Presynaptic α2δ subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual α2δ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of α2δ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABAARs. Strikingly, presynaptic α2δ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABAARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of α2δ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with α2δ-2 can modulate postsynaptic GABAAR abundance. Finally, exclusion of the alternatively spliced exon 23 of α2δ-2 is essential for the trans-synaptic mechanism. The novel function of α2δ-2 identified here may explain how abnormal α2δ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.SIGNIFICANCE STATEMENT Voltage-gated calcium channels regulate important neuronal functions such as synaptic transmission. α2δ subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual α2δ subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single α2δ variant can modulate synaptic connectivity and the localization of inhibitory postsynaptic receptors. Our findings provide basic insights into the development of specific synaptic connections between nerve cells and contribute to our understanding of normal nerve cell functions. Furthermore, the identified mechanism may explain how an altered expression of calcium channel subunits can result in aberrant neuronal wiring often associated with neuropsychiatric disorders such as autism or schizophrenia.

Dataset Information

Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

Publications

Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

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