Selective Loss of Smaller Spines in Schizophrenia

Abstract

Objective Deceased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large/mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. Here, we examined the density and volume of dendritic spines in deep layer 3 auditory cortex of 20 schizophrenia and matched control subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss. Methods Primary auditory cortex deep layer 3 spine density and volume was assessed in 20 pairs of schizophrenia and matched comparison subjects in an initial and replication cohort (12 and 8 pairs) by immunohistochemistry-confocal microscopy. Targeted Mass Spectrometry was used to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture. Findings Only the smallest spines are lost in deep layer 3 primary auditory cortex of schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, inversely correlated with the density of smaller, but not larger, spines in schizophrenia subjects. Consistent with this observation, CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures. Conclusion These findings require a rethinking of the over pruning hypothesis, demonstrate a link between small spine loss and a schizophrenia risk gene, and should spur more in-depth investigations of the mechanisms that govern new/small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia.

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

“…The spike-timing-dependent synaptic disconnection theory is an elaboration of these prior theories extending the synchrony deficits described at larger physical scales within the brain to the level of spiking neurons, considering the impact of spike timing disruption on synaptic connectivity operating through spike-timing-dependent plasticity mechanisms. Our data support the theory that activity-dependent retraction of dendritic spines (Lai and Ip, 2013), driven in part by a reduction in synchronous and near-synchronous spiking in prefrontal networks (Figures 2, 4, and 5), could contribute to the reduced density of dendritic spines on pyramidal cells that has been repeatedly observed in postmortem analysis of the brains of patients, particularly in prefrontal cortex (Glantz and Lewis, 2000; Kolluri et al, 2005; MacDonald et al, 2017; Shelton et al, 2015). …”

Circadian Rhythms of Perineuronal Net Composition

“…PNN deficits have been reported by several groups in the amygdala, entorhinal cortex, hippocampus, prefrontal cortex, and TRN in schizophrenia and bipolar disorder (Pantazopoulos et al, 2010a;Mauney et al, 2013;Pantazopoulos et al, 2014;Pantazopoulos et al, 2015;Enwright et al, 2016;Steullet et al, 2017). Disruption of PNNs in these disorders may alter rhythms of synaptic plasticity and in turn contribute to shared synaptic deficits (Penzes et al, 2011;Glausier and Lewis, 2013;Shelton et al, 2015;MacDonald et al, 2017). Such deficits may arise from disrupted memory consolidation processes allowing for decreased synaptic formation and/or increased synaptic pruning in brain regions involved in emotional memory processing.…”

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

“…For each of these disorders there is accumulating evidence that synaptic dysfunction is a hallmark of the pathophysiology of the disease. Neuroimaging and post-mortem studies of individuals with SCZ or BD show reduced brain volume and spine density, particularly in the prefrontal and anterior cingulate cortex and hippocampus relative to healthy controls [1][2][3][4] . These changes coincide with reduced protein and/or mRNA levels of various synaptic markers [5][6][7][8][9][10][11] .…”