Many essential body functions, including learning and memory, temperature control, and inflammatory responses, are regulated by the endocannabinoid system (ECS), a complex network of receptors and signals found throughout the brain. and the body. The ECS is activated when cannabinoid receptors are stimulated – a process that can occur when the body produces natural molecules called endocannabinoids or from the administration of cannabis.
In recent years, interest has grown in deciphering the role the ECS might play in the development of neurodevelopmental disorders such as autism spectrum disorders (ASD), and whether conditions that coexist with ASDs might be targeted. therapeutically.
To learn more about the link between endocannabinoids and ASDs and how innovative models are helping to study ECS and its effects on the developing brain, Technology networks talked to Drs. Karen Litwa and Ken Soderstrom from East Carolina University.
Anna MacDonald (AM): What do scientists know about the role of ECS in neurodevelopment and inflammatory responses?
Karen Litwa (KL): We know that the ECS is active during the early stages of embryonic growth and therefore plays an essential role in fetal brain development. There are two main cannabinoid receptors: CB1 and CB2. CB1 is mainly expressed in the central nervous system (CNS), while CB2 is present in cells of the immune system. In the brain, CB2 is almost exclusively expressed by microglia. Thus, the endocannabinoid system only serves as a link between the immune system and the CNS.
Given its abundance in the brain, ECS plays an important role in neurodevelopmental processes such as neurogenesis, neuronal specification and maturation, axonal pathway formation, glia formation, and neuronal migration. In other words, the ECS is essential to regulate the proper communication and plasticity of neurons to establish the complex circuitry that mediates many functions such as memory, appetite, anxiety, pain and learning.
AM: What is the link between the ECS and the development of neurodevelopmental disorders such as ASD?
KL: Over the years, observations in both animals and humans have implicated the ECS in the pathogenesis of ASD. In humans, postmortem brains of patients with ASD show reduced expression of CB1, while children with ASD have lower circulating levels of endocannabinoids. There is also a strong association between ASDs and endocannabinoid-synthesizing enzyme variants. Additionally, cannabis use during pregnancy is linked to an increased risk of ASD in the child, suggesting that disruption of endogenous ECS signaling may be involved in the pathogenesis. Evidence of ECS involvement continues to mount.
Although not the focus of our research, there is evidence suggesting a role for neuroinflammation in ASD. Elevated pro-inflammatory markers are a consistent finding in ASD and may even predict disease severity or phenotype. Researchers are particularly interested in studying whether microglia have sustained activity that results in the neurotoxicity seen in ASD.
Ruairi J Mackenzie (RM): Many people and groups with autism do not view their condition as something that needs to be treaty. However, a large part of the Literature still largely characterizes the behavioral characteristics of ASDs as symptoms. By targeting the endocannabinoid system, which characteristics of ASD would be addressed and which autistic individuals would such an approach be aimed at?
Ken Soderstrom (KS): Currently available treatments for ASD are generally complementary to behavioral strategies and individualized according to the intensity of the presentation. These treatments do not treat the condition itself, but rather the symptoms of co-occurring conditions (anxiety, attention deficit hyperactivity disorder, seizures, sleep disturbances, etc.) and treat behaviors that might impede development of a child.
Researchers expect that treatments targeting the ECS will provide similar benefits and may offer the possibility of developing safer and more effective therapies and improving the quality of life for people with ASD, not changing who they are. are as a person. A growing interest in cannabinoids, which act on the ECS, also opens doors to conditions other than ASD. An example is epilepsy, for which a cannabidiol preparation called Epidiolex received FDA approval in 2018.
Interestingly, epilepsy is also seen in a subset of ASD patients, a link that may further support the development of ECS-targeting treatments in ASD. An important feature of cannabinoid treatments is that some appear to treat multiple symptoms with a single preparation. For example, in addition to anti-epileptic activity, anecdotal evidence suggests that cannabidiol may also improve social behavior. There is also clear evidence that cannabidiol is anti-neuroinflammatory, which is a separate issue in ASD. This anti-inflammatory effect of cannabidiol is at least partly due to a potent inhibition of microglial activation, which researchers are working to better understand.
Although ECS-based therapies show promise, more research is needed to establish their efficacy and safety. To be clear, we do not endorse any particular treatment.
AM: What are some of the key challenges in studying the endocannabinoid system in the developing brain and the effects of its mediation?
KL: The study of embryonic brain development involves great complexity and presents many ethical barriers. Often with animal models of disease only a few of the defining features are replicated, meaning we are only looking at part of the larger picture, rarely the full disease. Neurodevelopmental disorders added challenges given their variable presentation and features such as verbal or non-verbal communication. These characteristics do not translate well in animal models and are therefore difficult to study.
AM: How do new models such as cortical spheroids help overcome these obstacles?
KL: Cortical spheroids, which are 3D in vitro models generated from induced pluripotent stem cells (iPSCs) mimic fetal brain development, which we otherwise do not have easy access to. These “mini-brain” models offer several advantages. The ECS is quite dynamic as the development of the fetus progresses, so it is important to consider the “age” of the brain we are modeling. With spheroids, cells grow over time, allowing researchers to estimate the window of development that the spheroid model represents. While the spheroids we used in our research modeled neurotypical control patients, they can also be cultured against the background of a person with ASD using iPSCs derived from patients with the disease. Cells self-organize to form functional neural circuits with spontaneous activity and supporting cells, such as astrocytes. Thus, they develop much like the human brain in uterowhich ensures that the relevant signaling pathways are intact.
The ECS is established in our spheroid model. We confirmed the expression of CB1 and of the enzymes necessary for the synthesis of endogenous ligands. Another useful feature of this model is that we can easily study the neural circuits that form using microelectrode array (MEA) technology. This tool allows us to measure and monitor the electrical activity of neurons over time or in response to a drug, a key variable for understanding neurodevelopmental diseases, possible interventions and their effects.
RM: What has your own research contributed to this growing field?
KL: Our research focuses specifically on the role of CB1 in controlling synaptic strength and the balance of inhibitory and excitatory signaling, which is altered in ASD. When we disrupted CB1 activity in our cortical spheroid model, we observed asynchronous neural network activity, similar to findings in ASD.
We used a compound that prevented signaling by the CB1 receptor. Using an MEA assay, we were able to measure localized activity (spikes) as well as rapid communication between cell populations (bursts). We observed a high degree of variability in spikes and bursts, suggesting a lack of synchronous activity and less mature neural circuitry. This find helps us understand the importance of intact CB1 signaling and how loss of signaling via this receptor produces a phenotype seen in ASD.
AM: Can you tell us about the current research on the use of cannabis and cannabidiol for ASD?
KS: Only two drugs, both focused on managing irritability, are FDA-approved for ASDs. But these drugs carry an increased risk of obesity and metabolic syndrome, which is why the search for new therapies is an important area of research. To date, however, only a few clinical studies have evaluated the use of cannabinoids as a treatment for ASD. It is important to note that the cannabinoids used in these studies were extracted and purified from botanical cannabis. These types of extracts contain at least traces of other bioactive molecules that potentially contribute to complex effects.
A recently published placebo-controlled study showed that cannabidiol preparations were well tolerated in ASD and had the potential to improve key symptoms like irritability. The side effect profile was favorable, with drowsiness and decreased appetite being the most common.
Cannabidivarin (CBDV) is another cannabidiol variant being studied to assess effects on irritability in children with ASD. The Children’s Hospital of Philadelphia (CHOP) initiated an observational registry study to gather information about the use of medical cannabis in the autistic pediatric population.
This is an emerging field with great potential. A challenge in targeting the ECS is to identify treatments that modulate the right balance of widely distributed cellular processes to achieve the desired effect. I’m certainly excited to see where the research is taking us, especially given the central role the ECS plays in the pathogenesis of ASDs.
Drs. Karen Litwa and Ken Soderstrom were talking to Anna MacDonald, Science Writer, and Ruairi J Mackenzie, Senior Science Writer for Technology Networks.