An Exploration of the FOXP2 Gene, Songbird Development, Human Language, and Autism

A genetic understanding of language development through cognitive and neurogenetic studies: an exploration of the FOXP2 gene, songbird development, human language, and autism

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Authors Attias, Lior Rivka

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Link to Item http://hdl.handle.net/10150/626743 A GENETIC UNDERSTANDING OF LANGUAGE DEVELOPMENT THROUGH COGNITIVE AND NEUROGENETIC STUDIES:

AN EXPLORATION OF THE FOXP2 GENE, SONGBIRD DEVELOPMENT, HUMAN LANGUAGE, AND AUTISM.

LIOR RIVKA ATTIAS

______

A Thesis Submitted to The Honors College

In Partial Fulfillment of the Bachelors degree With Honors in

Neuroscience and Cognitive Science

THE UNIVERSITY OF ARIZONA

DECEMBER 2017

Approved by:

______Dr. Konrad Zinsmaier Department of Neuroscience and Cognitive Science

A GENETIC UNDERSTANDING OF LANGUAGE DEVELOPMENT THROUGH COGNITIVE AND NEUROGENETIC STUDIES: AN EXPLORATION OF THE FOXP2 GENE, BIRD BRAINS, HUMAN LANGUAGE, AND AUTISM.

Lior Attias

December 2017

Neuroscience and Cognitive Science

Abstract

It is well known that FOXP2 has a connection to human language. In a familial case study of humans in one family with a mutated FOXP2, it was found that all members showed Developmental Verbal Dyspraxia, a cognitive language deficit. In knock out experiments in mice, it was found that FOXP2 is critical for Purkinje cell development in the brain as well as lung development. In FOXP2 knock out experiments in songbirds, it was found that songbirds could no longer learn new songs or cognitively understand song, which is used as a type of language in these animals. In knock in experiments with rats, it was found that rats with humanized FOXP2 show increased ability to switch between two central types of learning, a critical aspect of habit formation. It is thought that this habit formation is the basis of human language learning and development. Through a deep analysis of studies such as these, as well as of the genetic structure of FOXP2, it is hypothesized that the FOXP2 gene plays a critical role in allowing for appropriate connectivity on neurons in the brain, which could explain its role in language understanding and development, as well as its role in Autism in humans. A Genetic understanding of language development through cognitive and neurogenetic studies: an exploration of the FOXP2 gene, bird brains, human language, and autism.

Lior Attias Senior Thesis

Human development of language has obvious corollaries to that of songbird vocalization development. Human development of language is also dependent upon feedback loops that reduce error in the motor production of language (Andalman, Fee 2009). Additionally, the development of speech in humans occurs in stages, as does the development of song in songbirds. Both songbirds and humans develop their language through discrete phases, and corollaries for each phase can be found between humans and songbirds (Pearson et al 2014). Songbirds have an analogous phase to the human babbling phase, in which they vocalize only random sounds (Amy 2005). Songbirds also show the same development timeline as humans, slowly increasing the length of vocalizations and incorporating grammatical rules into their vocalizations as dictated by their species and by their exposure to other birdsongs. Songbirds continuously learn and develop their vocalizations, and this can be especially seen in the male- female vocalizations during mating season. Female responses to male courtship songs are variable and each contain specific meaning, revealing a highly differentiated signal system that is meaningful, follows grammatical rules, and relies on feedback (Amy 2005). Most importantly, the functional mechanism of language production is highly conserved, almost identical, between humans and songbirds (Pfenning et al 2014). FOXP2 forkhead transcription factor has been popularly linked with language development in songbirds in area X, the homologous structure to human’s basal ganglia (Pfenning et al 2014). Both the human basal ganglia and the bid area X have been shown to play a central role in speech development (Haesler et al 2007). While on first glance FOXP2 seems to be the “language gene” (Spiteri et al 2007), an analysis of the role of FOXP2 shows that FOXP2 is primarily a regulatory gene (Shu et al 2001). It is hypothesized that FOXP2 mediates language development indirectly via regulation of neurexin genes. Neurexins are presynaptic proteins that help connect, or “glue”, neurons together at the synapse (Südhof (2008). It is further hypothesized that FOXP2’s regulation of these genes has a global affect on neuronal development in both human and non-human systems—it is hypothesized that FOXP2 is a central regulator of all synaptic connections in the brain due to its regulation of neurexin proteins (Roll et al 2006). This change in perspective of the FOXP2 gene opens a discussion of FOXP2’s role in autism and other disorders stemming from inappropriate synaptic function and/or plasticity. FOXP2 has been shown to be strongly correlated with language development (Hurst et al 1990). In the seminal case study of a family pedigree, it was found that all members with a deletion of the FOXP2 gene presented with Developmental Verbal Dyspraxia (DVS) (Hurst et al 1990), a motor disorder characterized by the failure of the physical act of production of speech due to neuromuscular defects (Barrett 1999). DVS is not characterized by a physical inability to produce language, it is purely a cognitive deficit (Barrett 1999). It belongs to a family of language disorders called Specific Language Impairment, which are language disorders that are not caused by psychological or physical traits, but rather solely arise from defects in neurological language production mechanisms (Barret 1999). Notably, while DVS patients seem to cognitively understand language, they cannot comprehend grammar (Haesler 2007). Additionally, during the original analysis of the family pedigree, it was discovered that DVS is inherited via Mendelian (monogenetic) autosomal dominant inheritence (Fisher 2003). FOXP2 is a transcription factor (Gascoyne 2015). It shares biochemical characteristics with other members of the FOXP transcription factor family, including a C-terminal winged forkhead DNA binding domain, and acts as a transcriptional repressor (Gascoyne 2015; Shu 2001; Spiteri 2007; Vernes 2007). FOXP2 is not neuronally restricted; it has been observed in developing lung epithelium, intestinal tissue, and cardiac tissue (Gascoyne 2015; Shu 2001). FOXP2 has been identified in malignant myeloma cells, which are B-cells that terminally differentiated into plasma cells, that lack FOXP1, its close genetic cousin (Gascoyne 2015). In summary, FOXP2 is part of a family of regulatory transcription factors that have been linked to the regulation of the cell cycle. In Gascoyne’s 2015 study, it was shown that FOXP2 regulates the cyclin-dependent kinase inhibitor p21WAF1/C1P1, which means that FOXP2 causes growth arrest of osteosarcoma cells by inhibiting growth factors. This is noteworthy because it has been shown that the growth factors used by neurons to increase and strengthen synaptic connections are used by cancer cells to proliferate inappropriate growth and division (Mancino 2011). In the brain, FOXP2 down-regulates CNTNAP2, interacts with CTBP1 and CTBP2 which are co-repressors for multiple transcription factors, and transcriptionally represses the SRPX2 gene promoter (Estruch 2016). A mutated SRPX2 gene causes speech dyspraxia and mental retardation (Roll 2006). It is the interaction of the FOXP2 gene with these additional genetic factors that allows for speech development. For this reason, it is often said that FOXP2 is not correlated with language development or autism (Newbury 2002). It is known that language impairments have a wide variation of genetic and neurological causes (Newbury 2010). There is strong evidence that FOXP2 along with its co-regulatory genes do play an active role in language development and neuroplasticity (Estruch 2016). A study by Yang et al in 2010 wanted to explore the effects of a complete FOXP2 knock out. A mice model was chosen because mice have two copies of FOXP2, similar to in humans, but the mice FOXP2 gene has two amino acid substitutions. In this study, a complete knockout of FOXP2 in mice showed that it is required for proper brain and lung development (Yang et al 2010). After knocking out the gene in mice, it was found that the mice with no functional copies of FOXP2 showed severe abnormalities in the Prunkinje layer. These mice also died an average of 21 days after birth from inadequate lung development. This knockout experiment suggests that FOXP2 plays a central role in the general development of cells. For this reason, the complete knockout mouse model has been used to examine FOXP2’s role in brain development. Many species including mice (Grozer 2008), chimpanzees, and gorillas contain variations of the FOXP2 gene (Carrol 2005). The FOXP2 gene in mice differs by two amino acids from the FOXP2 gene in humans. These two substitutions were introduced into the endogenous FOXP2 gene of mice to generate a “humanized” mouse FOXP2 gene. The mutated mice showed more rapid acquisition of stimulus-response associations than wild-type mice when declarative (location-based) and procedural (response-based) forms of learning could interfere with each other during the learning of procedures (Schreiweis 2014). This was tested via a series of maze trials. One group WT and mutant mice went through a maze with spatial cues, promoting declarative or spatial learning, and another group of WT and mutant mice went through a maze of without spatial cues, promoting response-based or procedural learning. In the maze promoting spatial learning, the mutant mice learned faster than the WT. In the other maze, there was no statistically significant difference (see figure 1). This suggests that humanized FOXP2 plays a role in spatial learning. Additionally, the ability of the mice to switch from declarative to procedural learning was tested. After training on the two maze types, mice were put into a maze which required them to learn via location in some parts, and learn via responses in another part. The WT mice took significantly longer than the mutants to make the switch between these two types of learning (see figure 2). This implies that humanized FOXP2 mitigated the competitive interactions between the two learning systems. The transition from declarative to procedural learning is proposed to occur during striatum-dependent habit learning, which is considered a central part of language learning (Shreiweis 2014). The mutant mice also showed significant differences in their cortico- basal ganglia circuits, in accordance with increased spatial learning ability. They also showed differences in long term depression that was location-dependent. LTD was stronger in the mutant mice in the dorsolateral striatum, but was weaker in the dorsomedial striatum, implying that FOXP2 has location-dependent expression (Shreiweis 2014). These results highlight the role of FOXP2 in learning and forming habits, a central aspect of language acquisition, and implies that FOXP2 has a role in the synaptic relationships between neurons. The genes that FOXP2 directly interacts with have an often direct correlation with the behavioral phenotype of Specific Language Disorders. An inappropriate expression of the CNTNAP2 gene is directly linked to autism (Newbury 2010). CNTNAP2 is a gene that encodes for a CASPR2, a protein in the neurexin family (Rodenas-Cuadrado 2013). Neurexin function in vertebrate nervous systems as cell adhesion molecules and receptors. Most notably, neurexins act predominately at the presynaptic terminal of neurons (Reissner et al 2013). They connect pre-synaptic and post-synaptic neurons at the synapse (Sudhof 2008). CASPR2 specifically is a single-pass transmembrane protein, and is distinguished from most other neurexins by an extracellular neuropilin homology domain and a fibrinogen-like region. These additional domains mediate cell-cell adhesion. Additionally, the extracellular region of CASPR2 has two epidermal growth-factor like domains. These domains facilitate receptor-ligand interactions mediating synaptic differentiation (Rodenas-Cuadrado 2013). This means that CASPR2 is especially able to strengthen synapses between the post and presynaptic neuron. CASPR2 functions like most other neurexins. It acts similarly to the positive feedback found in AMPA-NMDA receptor relationships. Neurexins are made up of two protiens—�- neurexin and �-neurexin. Neurexins are localized at the terminal via the alpha and beta sub- proteins and span the membrane to interact postsynaptic receptors (Sudhof 2008), one of which is called a neuroligin. These transmembrane molecules bind together to promote adhesion between dendrites and axons (Dean 2005). Additionally, it was found that binding of neurexin to neuroligin signals the recruitment of other presynaptic and postsynaptic molecules that form a functional synapse (Dean 2005). It was also found that Neurexins alone can induce postsynaptic differentiation and clustering of neuroligin receptors. Similarly, it was found that neuroligins alone can induce the formation of fully functional presynaptic terminals in connecting axons (Dean 2005). Thus, the neurexin-neuroligin interaction does not only connect two cells at a synapse, it also can trigger synapse formation both from the presynaptic cell and from the post synaptic cell (Dean 2005). This makes the neurexin proteins uniquely powerful in controlling the creation of synapses, which may explain the increased ability for learning in the mutant FOXP2 mice in the Shreiweis experiment. FOXP2 regulates the CNTNAP2 gene, which transcribes the CASPR2 neurexin, which is responsible for linking two cells at a synapse as well as induce synaptic formation. Thus, it is possible that the ability of FOXP2 to indirectly mediate synaptic differentiation may underlie human development of language. This hypothesis has been explored through the use of animal models that share speech-like characteristics with humans. Through these studies it is possible to further understand FOXP2’s impact on language as well as the biochemical mechanism of synaptic strengthening via FOXP2 and CNTNAP2 (Sudhof 2008; Shreiweis 2014; Hillard 2012; Pfenning 2014). In studying the effects on the FOXP2 gene, it is necessary to work with animal models that have neuronal circuitry that closely resemble human production of language (Pfenning et al 2014; Hillard 2012). Songbirds behaviorally model both the cognitive mechanisms of human production of speech as well as the functional structural processes involved in language production (Pfenning et al 2014; Hillard 2012). In their production of song, songbirds have a functional corollary to humans. In songbirds, area X is a basal ganglia nucleus that is required for vocal learning (Pearson 2008). Area X has the same function as the human basal ganglia in terms of language production. It also shows remarkable structural similarity to the human basal ganglia in its neural circuitry (Pearson 2008). In a study by Andalman in 2009, researchers used disruptive auditory feedback to induced learned changes in the song of a songbird. It was found that the Anterior Forebrain Pathway circuit, a circuit within the basal ganglia (Area X) in songbirds, was responsible for feedback upon vocalizations, allowing the bird to reduce error with every song repletion. Each feedback disruption phase was conducted over only a few hours, and it was found that this learning is fast and long lasting—changes to the AFP were incorporated within one day of learning a new song. Hence, Area X in songbirds allows for feedback loops leading to improved motor production of vocalizations through development (Andalman 2009). Andalman concluded that while the exact mechanism of the connection between the basal ganglia and motor learning was not completely understood, there was strong evidence to suggest that basal ganglia are necessary to express recently learned behavior, and that changes in neuronal activity in response to learning first appear in basal ganglia circuits (Andalman 2009). These findings were correlated with past studies about basal ganglia function in humans (Atallah 2007). In a study by Haesler et al in 2007, a genetic knockdown of the FOXP2 gene in the basal ganglia nucleus (Area X) was performed. Haesler previously hypothesized that when zebra finches learn a new song, both as developing young birds and as mature adults changing their song seasonally, FOXP2 levels were upregulated in Area X (Haesler 2007). Building on this finding, the researchers performed a genetic knock down of the FOXP2 gene via virus-mediated RNA interference in Area X of the zebra finches. The birds were tested before and after the KD, and it was found that the birds without reduced FOXP2 activity could not successfully imitate vocalizations by other birds—their imitations were incomplete and inaccurate. The birds showed similar speech abnormalities to humans with DVD: inappropriate mouth (beak) movements. Multiple studies have shown that Area X is functionally and structurally analogous to the human basal ganglia, and is heavily involved in feedback loops reducing error in motor production of vocalizations. The Haesler study showed that FOXP2 is a necessary constituent for proper learning of new vocalizations. Haesler found that the KD of FOXP2 did not cause damage to Area X or cell death, nor did it alter the density of neurons in the basal ganglia nucleus. Additionally, imitations of vocalizations did not have the same errors as those of birds with lesions in Area X, allowing the conclusion that FOXP2 affects the circuitry and its plasticity in the brain region. In other words, birds without FOXP2 could not learn to sing. They could not learn to modify their motor movements in the AFP circuit, and without their feedback loop they could not produce grammatically coherent vocalizations. FOXP2’s role in synaptic plasticity is echoed both in the Haesler study as well as in the Schreiweis rat maze study. The Haesler study, which used a FOXP2 KD, showed that FOXP2 was necessary for synaptic circuitry and/or plasticity in the basal ganglia. The Schreiweis study, which used a FOXP2 knock in, showed that the human FOXP2 gene increases the spatial learning skills as well as increased flexibility in switching from procedural to spatial learning. All of these experiments fit with the biochemical pathway of FOXP2 inhibiting the CNTNAP2 gene which transcribes the CASPR2 neurexin, which not only binds but also creates synapses between two neurons. Putting this information together is interesting. We see that mutations in the two copies of FOXP2 affect vocalizations (as seen in the songbird model). Mutations in one copy resulted in reduced speech (as seen by the songbird model), while mutations in both copies cause major brain development issues (as seen by the complete KO mouse model). I argue that pathway of FOXP2 is critical to a modern understanding of synapses and synaptic plasticity. It is known that the presence of FOXP2 downregulates, rather than upregulates, the CNTNAP2 gene. For many cognitive experience, it is known that the brain detects differences between neuronal stimuli. The experience of sight arises from differences in activation of photoreceptors. The experience of touch, taste, and pain all arise from different levels of activation of periphery neurons. The brain down regulates the level of neuronal activity in order to produce greater differences between incoming stimuli. The experience of sound arises from differences in the activation of hair cells. One proposed explanation for the language deficits associated with a lack of FOXP2 is that there is not enough difference in synaptic connections-- the deficits could arise from too many synaptic connects leading to undifferentiable inputs to the brain. While further exploration is needed, the existence of the FOXP2 gene urges a new way to understand synaptic formation and degradation. If FOXP2 is indeed critically involved in synaptic formation, the implications on synaptic plasticity are enormous. If a lack of FOXP2 does in fact lead to an over production of synapses, it could mean that autism is tied to an overproduction of inputs to the brain. It could mean that the correlation between language deficits and autism spectrum disorders is not a coincidence, but rather show that both are affected by the same mechanisms. There are many questions to still be asked; the discovery of the FOXP2 gene is one that could lead to many more answers, and many more questions, in the future of neuroscience and cognitive science.

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