Dendritic structural plasticity and neuropsychiatric disease

Abstract

The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity. In this Review, we discuss the importance of recent genetic findings on the different mechanisms of structural plasticity and propose that these converge on shared pathways that can be targeted with novel therapeutics.

Figure 1|. Spine and dendrite development in health and disease.

a,b| Timeline of the principal cellular events occurring during human brain development^, and their coincidence with neuropsychiatric diseases of varying onset. Morphological events regulating dendritic structure that are discussed in this Review are highlighted in green. Intellectual disability usually presents in early infancy or early childhood, although in some cases, it cannot be formally diagnosed until later (when standardized tests can be implemented). Epilepsy encompasses a broad range of seizure disorders, each with their own typical age of onset. Here, we focus on genetic forms of epilepsy that have their onset largely in the age range depicted (see REF. for review). The symptoms of autism spectrum disorder (ASD) are recognized early in development and are noticeable in the first few years of life. These early-onset disorders overlap with the developmental processes of dendritic growth and spine morphogenesis. Bipolar disorder and schizophrenia are late-onset neurodevelopmental disorders that appear in late adolescence or adulthood, coinciding with the biological process of spine pruning. c | Putative developmental trajectories of spine development during typical development or in neuropsychiatric disorders, predicted from post-mortem studies. Studies have found that spine density is reduced in intellectual disability and increased in ASD, which may suggest a developmental alteration in spine morphogenesis. Spine and dendrite loss in epilepsy is thought to be caused by the onset of seizures and is depicted as a sharp decline in spine density (however, a primary defect in spine density before seizure onset cannot be excluded). Schizophrenia and bipolar disorder are associated with fewer dendritic spines post-mortem^,, possibly caused by excessive spine pruning. d | Genetic and environmental risk factors for neuropsychiatric disorders are hypothesized to converge on a subset of genetic networks and pathways that regulate dendritic structure and alter the synaptic input field. Both hypoconnected and hyperconnected cells disrupt local and distal connectivity in the brain. Depending on the brain regions affected, this will impact different psychological domains (here, we use the National Institutes of Health Research Domain Criteria (RDoC) relevant to neuropsychiatric disorders; see ‘Related links’). CNV, copy number variant; GWAS, genome-wide association study; mo, month; SNP, single-nucleotide polymorphism; SNV, single-nucleotide variation.

Figure 2|. Mechanisms of structural plasticity.

a | Hebbian synaptic plasticity mechanisms^,. High-frequency synaptic activity associated with high calcium entry causes long-term potentiation (LTP), which induces spine growth, an enlargement of the postsynaptic density (PSD) and actin polymerization and promotes the surface expression of AMPA receptors (AMPARs). Low-frequency synaptic activity associated with modest calcium entry through NMDA receptors (NMDARs) causes long-term depression (LTD), which induces shrinking of the spine and PSD, actin depolymerization and a reduction of surface AMPAR expression. b | Proposed mechanisms of homeostatic synaptic plasticity. Synaptic scaling is a form of homeostatic plasticity that allows neurons to modify their overall synaptic input (excitability) in response to changes in circuit activity. Activity deprivation causes neurons to scale up, proportionally strengthening synapses by increasing surface AMPAR expression to increase overall synaptic input. Studies have shown that activity blockade in vitro and activity deprivation in vivo can also cause an increase in spine size (or density)^,,. Prolonged circuit activity causes neurons to scale down, proportionally reducing synaptic strength by removal of surface AMPARs. Prolonged activity during seizures also reduces the size and number of spines^,, opposing the morphological effects of activity deprivation. c | Summary of mechanisms that can regulate spine development and plasticity. Spine growth can be induced by LTP or scaling up and is associated with spine stability, reduced spine dynamics, increased synaptic strength and increased surface AMPAR expression. Spine shrinkage can be induced by LTD or scaling down and is associated with spine destabilization, possibly leading to elimination or pruning of spines, synaptic weakening and a reduction of surface AMPAR expression.

Figure 3|. Neuropsychiatric risk factors and biological pathways regulating structural plasticity.

a |Schematic illustration of a systems biology approach for identifying novel genes likely to affect spine plasticity in neuropsychiatric disorders. Exome sequencing studies of de novo variants are particularly useful for uncovering genetic risk networks involved in different disorders. Although many genes discovered in exome sequencing studies are individually nonsignificant, as a whole, they can reveal a mutational spectrum for each disorder and provide clues for the underlying pathways and networks involved in pathogenesis. In particular, genes with de novo mutations for which the protein products localize to the postsynaptic density (PSD) are excellent candidates for future studies on the dysfunctional pathways altering structural plasticity in neuropsychiatric disorders. To highlight such genes, de novo mutations affecting protein coding for each disorder were intersected with proteins present in the human PSD proteome (a proxy for the dendritic spine). The number of genes in each overlap is indicated (top panels). All of the de novo data were obtained from denovo-db (see ‘Related links’) accessed on 21 September 2017. Additional studies for schizophrenia^– that were not in the denovo-db were obtained from supplementary data compiled in REF. Only de novo variants affecting protein-coding regions or splice sites were included (that is, missense, frameshift and splice site mutations, altered stop codons, altered start codons, insertions and deletions). Human PSD proteome data were obtained from REF. . Gene ontologies (GOs) were then used to classify PSD-associated mutations into biological processes relevant to spine structure and function. To do so, GO categories from each data set were defined in DAVID (see ‘Related links’) v6.8, accessed on 11 November 2017, using the functional annotation chart. Homo sapiens was used as a background, and the ‘biological process’ ontology (GOTERM_BP_FAT) was used to annotate gene lists. The following ontologies were used to cluster genes into functional pathways: cell adhesion (GO:0007155-cell adhesion), GluR signalling (GO:0007215-glutamate signalling pathway), calcium (GO:0006816-calcium ion transport) and GTPase (G00043087-regulation of GTPase activity). This analysis shows that the de novo mutations affecting PSD proteins cluster into distinct biological pathways to varying degrees, providing an overview of the contribution of each pathway to each disorder (bottom panels). The percentage of genes in each GO category is depicted on the y-axis. Exome sequencing data for bipolar disorder are currently insufficient to classify mutations into categories. b | Illustration of a dendritic spine containing different functional groups of neuropsychiatric-disorder-associated risk factors (TABLE 1) that regulate spine structure. Functional groups are colour coded. ANK3, ankyrin 3; ARHGEF9, Rho guanine nucleotide exchange factor 9; ASD, autism spectrum disorder; CACNA1C, voltage-gated calcium channel subunit-α1Cav1.2; CACNG2, voltage-dependent calcium channel-γ2 subunit; CACNB4, calcium channel voltage-dependent subunit-β4; CAMK2A/B, calcium/calmodulin-dependent protein kinase type II subunit-α/β; CASK, calcium/calmodulin-dependent serine protein kinase; CNTNAP2, contactin-associated protein-like 2; DLG4, disks large homologue 4; DLGAP1, disks large-associated protein 1; GRIA1/2, glutamate receptor ionotropic, AMPA1/2; GRIN2A/B, glutamate receptor ionotropic NMDA2A/B; KALRN, kalirin; NF1, neurofibromin 1; NLGN3, neuroligin 3; NRXN1, neurexin 1; PRRT2, proline-rich transmembrane protein 2; RAC1, RAS-related C3 botulinum toxin substrate 1; SHANK3, SH3 and multiple ankyrin repeat domains protein 3; SYNGAP1, RAS/RAP GTPase-activating protein SynGAP 1; TRIO, triple functional domain protein.

Figure 4|. Pharmacological targets and associated structural pathways within the dendritic spine.

Within the dendritic spine, AMPA receptors (AMPARs) govern fast synaptic transmission in response to glutamatergic signalling. Glutamate binds to, and activates, AMPARs in response to synaptic activity. The resulting influx of sodium and potassium ions through the open channel results in depolarization. NMDA receptor (NMDAR) activation occurs in response to glycine and glutamate binding concurrently with depolarization. In addition, depolarization results in the opening of voltage-gated calcium channels (VGCCs; including L-type, Ca_v1.2/1.3-containing channels). Depolarization and VGCC activation result in brain-derived neurotrophic factor (BDNF) exocytosis. Calcium influx activates calcium/calmodulin-dependent kinase type II (CAMKII), resulting in activation of GTPase signalling by phosphorylation of kalirin and/ or triple functional domain protein (TRIO). These guanine nucleotide exchange factors regulate RAS-related C3 botulinum toxin substrate 1 (RAC)/transforming protein RhoA (RHOA) to alter cytoskeletal dynamics. GTPase activation can either increase (RAC pathway) or decrease (RHOA pathway) actin polymerization through serine/threonine protein kinase PAK (PAK) or Rho-associated protein kinase (ROCK) pathways to promote spine growth or retraction, respectively^,. In addition, calcium results in the activation of eukaryotic elongation factor 2 kinase (eEF2K), phosphorylation of elongation factor 2 (EF2) at Thr56 (REF. 192) and inhibition of BDNF translation at ribosomes. BDNF release results in the activation of the BDNF/NT3 growth factor receptor (TRKB; also known as NTRK2) and induction of the RAS pathway through growth factor receptor-bound protein 2 (GRB2) and son of sevenless homologue 1 (SOS1; not shown), which in turn activates the phosphatidylinositol 3-kinase (PI3K) and MEK (MAPK/ERK kinase) and/ or extracellular-signal-regulated kinase (ERK) pathways, contributing to long-term potentiation via AMPAR trafficking and membrane insertion within the spine. Many regulatory compounds targeting key synaptic signalling proteins have been isolated (indicated in the pink boxes). These, or other related small molecules, may have utility in neuropsychiatric disorders by regulating synaptic function and spine dynamics. CCBs, calcium channel blockers; FTIs, farnesyl transferase inhibitors; mTOR, mammalian target of rapamycin; PAM, positive allosteric modulator; TARP, transmembrane AMPAR regulator protein. TRIPα, TRIO inhibitory aptamer; Question mark indicates unknown mechanism.