The serotonergic system regulates numerous behaviours and disruptions in this system have been associated with disorders of mood and mind. Although molecular genetic analysis has dissected many of the genes involved in the specification of the serotonergic system, relatively little is known about the mechanisms that promote axonal outgrowth from serotonin-producing neurons and how these projections are directed to innervate and form synapses with their appropriate targets. The mouse anorexia mutation causes hypersprouting of serotonergic projections in target fields and has provided us the unique opportunity to examine the crucial events that lead to the establishment of these complex serotonergic networks. Through positional cloning, I have identified a candidate gene that is upregulated during a time in which innervation and synaptogenesis of serotonergic neurons are maximal. I have assessed the expression of this candidate gene in the brain and have found striking differences in the pattern of expression between the normal and the mutant mouse. Furthermore, by using transgenic methods, I have partially rescued several hallmark behavioural phenotypes in the mutant mouse. Thus, this candidate almost certainly represents the “Anorexia” gene.

Reading Disabilities (RD) and Attention Deficit/Hyperactivity Disorder (ADHD) are common neurodevelopmental disorders with evidence for shared genetic etiology. This study examined four predicted neuronal migration genes in RD (DCDC2, KIAA0319, DCDC2B and NEDD4L), and three of these genes in ADHD (DCDC2, DCDC2B and NEDD4L). Putative regulatory elements of DCDC2 (6p) and KIAA0319 (6p) were screened to identify functional risk variants that explain previous association findings. No statistically significant associations were observed in DCDC2. In KIAA0319, variants with predicted regulatory function showed association with RD. This supports the hypothesis that causal RD risk variants in KIAA0319 alter gene expression. DCDC2B (1p), the homolog of DCDC2, showed suggestive evidence for association to ADHD, but not RD. Previous association findings in NEDD4L (18q) could not be replicated. No pleiotropic gene for RD and ADHD was identified. However, together with previous findings, this study supports that neuronal migration may be a common underlying deficit in both RD and ADHD.

Egg-laying decisions can have significant fitness consequences. In female Drosophila melanogaster, egg-laying involves foraging-like behaviour. Natural allelic variation in foraging (for) underlies the rover/sitter foraging behaviour polymorphism found in D. melanogaster. for encodes a cGMP-dependent protein kinase (PKG) where rovers have higher for-PKG transcript levels and PKG activity than sitters. Interestingly, the orthologue of for in nematodes (egl-4) affects both egg-laying and foraging behaviours. When given a choice between low- and high-nutrient patches, rovers preferentially lay more eggs on the low-nutrient patches while sitters and a sitter mutant prefer high-nutrient patches. Using the neuronal driver elav-GAL4, rover-like preferences were rescued in sitter flies. Compared to sitters, rovers have higher fitness on a sub-optimal substrate which may explain the observed egg-laying preferences. By studying the link from genes to behaviour, this study provides insight to the evolutionary basis and maintenance of behaviour.

Background: Antisocial behaviours in adolescents are costly in social and financial terms. These behaviours are heritable and genetic variants may be contributing factors. The purpose of this study was to determine whether genetic variants regulating the oxytocin-vasopressin (OXT-AVP) system were associated with aggressive behaviours. Methods: A sample of children displaying extreme, persistent and pervasive aggressive behaviours was first compared to adult controls (160 cases-160 controls) and then to child controls (182 cases-182 controls). We also tested for interactions between oxytocin receptor (OXTR) single nucleotide polymorphisms (SNPs) and serotoninergic polymorphism, 5-HTTLPR. Results: Using adult controls, OXTR SNPs rs6770632 and rs1042778 were associated with aggressive behaviours in females and males, respectively. However, using child controls revealed significant effects of AVPR1A rs11174811 in females; OXTR rs237898, rs237902 and AVP rs3761249 in males. There were no significant interactions between 5-HTTLPR and OXTR SNPs to predict aggression. Conclusion: OXT-AVP SNPs may be associated with aggressive behaviours.

Differential gene expression between sexes is the main contributor of the morphological and behavioral differences observed between them. Studying the signatures of these differences at the genetic level will help us understand the forces acting on them. The existence of androdioecious and gonochoristic species in the genus Caenorhabditis makes it suitable for sex-biased gene expression studies. In this thesis, I have assembled the transcriptome of C. sp. 9 and C. sp. 5 using de novo and reference-based techniques. Evolutionary analysis of the assembled contigs showed that genes with male-biased expression evolve faster than those with a female bias, as observed in other taxa. Furthermore, I found a positive correlation between gene expression and codon usage bias.

Reading Disabilities (RD) and Attention Deficit/Hyperactivity Disorder (ADHD) are common neurodevelopmental disorders with evidence for shared genetic etiology. This study examined four predicted neuronal migration genes in RD (DCDC2, KIAA0319, DCDC2B and NEDD4L), and three of these genes in ADHD (DCDC2, DCDC2B and NEDD4L). Putative regulatory elements of DCDC2 (6p) and KIAA0319 (6p) were screened to identify functional risk variants that explain previous association findings. No statistically significant associations were observed in DCDC2. In KIAA0319, variants with predicted regulatory function showed association with RD. This supports the hypothesis that causal RD risk variants in KIAA0319 alter gene expression. DCDC2B (1p), the homolog of DCDC2, showed suggestive evidence for association to ADHD, but not RD. Previous association findings in NEDD4L (18q) could not be replicated. No pleiotropic gene for RD and ADHD was identified. However, together with previous findings, this study supports that neuronal migration may be a common underlying deficit in both RD and ADHD.

Egg-laying decisions can have significant fitness consequences. In female Drosophila melanogaster, egg-laying involves foraging-like behaviour. Natural allelic variation in foraging (for) underlies the rover/sitter foraging behaviour polymorphism found in D. melanogaster. for encodes a cGMP-dependent protein kinase (PKG) where rovers have higher for-PKG transcript levels and PKG activity than sitters. Interestingly, the orthologue of for in nematodes (egl-4) affects both egg-laying and foraging behaviours. When given a choice between low- and high-nutrient patches, rovers preferentially lay more eggs on the low-nutrient patches while sitters and a sitter mutant prefer high-nutrient patches. Using the neuronal driver elav-GAL4, rover-like preferences were rescued in sitter flies. Compared to sitters, rovers have higher fitness on a sub-optimal substrate which may explain the observed egg-laying preferences. By studying the link from genes to behaviour, this study provides insight to the evolutionary basis and maintenance of behaviour.

Background: Antisocial behaviours in adolescents are costly in social and financial terms. These behaviours are heritable and genetic variants may be contributing factors. The purpose of this study was to determine whether genetic variants regulating the oxytocin-vasopressin (OXT-AVP) system were associated with aggressive behaviours. Methods: A sample of children displaying extreme, persistent and pervasive aggressive behaviours was first compared to adult controls (160 cases-160 controls) and then to child controls (182 cases-182 controls). We also tested for interactions between oxytocin receptor (OXTR) single nucleotide polymorphisms (SNPs) and serotoninergic polymorphism, 5-HTTLPR. Results: Using adult controls, OXTR SNPs rs6770632 and rs1042778 were associated with aggressive behaviours in females and males, respectively. However, using child controls revealed significant effects of AVPR1A rs11174811 in females; OXTR rs237898, rs237902 and AVP rs3761249 in males. There were no significant interactions between 5-HTTLPR and OXTR SNPs to predict aggression. Conclusion: OXT-AVP SNPs may be associated with aggressive behaviours.

The serotonergic system regulates numerous behaviours and disruptions in this system have been associated with disorders of mood and mind. Although molecular genetic analysis has dissected many of the genes involved in the specification of the serotonergic system, relatively little is known about the mechanisms that promote axonal outgrowth from serotonin-producing neurons and how these projections are directed to innervate and form synapses with their appropriate targets. The mouse anorexia mutation causes hypersprouting of serotonergic projections in target fields and has provided us the unique opportunity to examine the crucial events that lead to the establishment of these complex serotonergic networks. Through positional cloning, I have identified a candidate gene that is upregulated during a time in which innervation and synaptogenesis of serotonergic neurons are maximal. I have assessed the expression of this candidate gene in the brain and have found striking differences in the pattern of expression between the normal and the mutant mouse. Furthermore, by using transgenic methods, I have partially rescued several hallmark behavioural phenotypes in the mutant mouse. Thus, this candidate almost certainly represents the “Anorexia” gene.

The chemical synapse is an asymmetric structure consisting of presynaptic and postsynaptic terminals in direct apposition to each other. Synapses function to mediate the transmission of signals between neurons and their targets. The formation of synapses is a tightly regulated process requiring the interaction of many genes and molecular pathways. I am interested in identifying genes and signaling pathways that are required for proper synapse formation. Using the GABAergic neuromuscular junctions of C. elegans as a model system, I have identified fsn-1 (F-box synaptic protein), a gene required for the control of synaptic growth. fsn-1 mutants exhibit a synaptic defect characterized by both synaptic over differentiation and under differentiation. FSN-1 is an F-box protein with a SPRY (SPla and RYanodine receptor) domain that functions cell-autonomously in neurons to regulate synaptic growth. I have shown that it functions in an E3 ubiquitin ligase-like complex with the RING-H2 finger protein RPM-1 (Regulator of presynaptic morphology), SKR-1 and Cullin. The composition of this complex is similar to SCF (Skp1, Cullin, F-box) E3 ubiquitin ligases. We hypothesize that this complex controls synapse formation by down regulating synapse promoting factors through an ubiquitin mediated process. We have identified two receptor tyrosine kinases that genetically interact with fsn-1, the Anaplastic Lymphoma Kinase homolog SCD-2 (Suppressor of Constitutive Dauer) and the C. elegans insulin receptor DAF-2 (abnormal DAuer Formation). Loss of function mutations in scd-2 or daf-2 partially suppress the synaptic differentiation defects of fsn-1 mutants, suggesting that they participate in signaling pathways whose activities are normally inhibited by FSN-1 during synapse formation. Unlike FSN-1 that functions in GABAergic neurons, I found that SCD-2 and DAF-2 have cell non-autonomous functions at GABAergic neuromuscular junctions. SCD-2 is required in the nervous system in the RID interneuron where it could modulate synapse formation through ligands present on the motoneuron cell surface. The DAF-2/insulin pathway functions in postsynaptic muscle cells to regulate FSN-1 dependent presynaptic growth likely through a retrograde or feedback mechanism. I propose a model where FSN-1 regulates synapse formation by attenuating signals that converge upon the presynaptic terminal to stimulate or inhibit synaptic growth.