Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

Abstract

The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra

“…Sources of GABAergic afferents to the SN include neurons that comprise the striatal direct pathway and neurons in the globus pallidus externus (Haber and Fudge, 1997). Schizophrenia subjects exhibit increased striatal glutamate tone (de la Fuente-Sandoval et al, 2011 and number of glutamatergic synapses in comparison with NCs McCollum et al, 2015; Figure 4a). It is possible that the extra stimulation provided by the glutamatergic input onto the GABAergic striatal neurons produces an increase in GAD and GABA in the SN.…”

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

“…Recent postmortem studies have suggested glutamatergic input to this region is increased. 6,7 The NMDA receptor and group 1 mGluRs are primary glutamatergic receptors expressed on striatal neurons and are important for neuronal signalling and neurotransmitter tone. In the present study we show that protein expression of the NMDA receptor subunits (NR1, NR2A and NR2B), group 1 mGluRs (total, dimeric and monomeric forms) and group 1 mGluR regulators (Norbin and Homer1b/c) are not altered in the NAcc in individuals who had schizophrenia, which is in contrast to previous reports on cortical and hippocampal brain regions.…”

“…McCollum and colleagues 7 reported an increase in asymmetric glutamatergic synapse number in the NAcc in a separate schizophrenia cohort, a finding that was specific to the core and not the shell of the NAcc, accompanied by a reduction in the area of the postsynaptic density (PSD) in asymmetric synapses. Furthermore, alterations of PSD membrane-associated guanylate kinases (MAGUK), SAP-102 and SAPAP1 expression have also been observed in the NAcc of schizophrenia cohorts, 40,41 suggesting alterations of scaffolding and signalling proteins within postsynaptic sites of the NAcc in schizophrenia pathology.…”

“…McCollum and colleagues 7 reported the increased density of characteristic glutamatergic synapses, in addition to a reduction in postsynaptic density. However, these changes were specific to the core and not the shell of the NAcc, suggesting subregional differences.…”

“…6 In support of this finding, increased asymmetric synapses, representative of glutamatergic projections, have been observed within the core of the NAcc in individuals with schizophrenia. 7 Furthermore, these synapses were observed to have reduced postsynaptic density area. Taken together, these recent studies suggest that altered glutamatergic neurotransmission to the NAcc is associated with schizophrenia pathology; however, further evidence characterizing the glutamatergic system within the NAcc in individuals with schizophrenia is required.…”