THC Paper #2

Short answer questions:

  1. How did prenatal THC affect hippocampal plasticity markers?

    1. Increasing NR1 (NMDA receptor subunit), mGluR5, Homer 1, CB1 receptor, and HINT1.

Decreasing NR2A (NMDA subunit) and PSD95.

This pattern reflects excitatory/inhibitory imbalance, altered glutamatergic signalling, and disrupted synaptic stabilization in the hippocampus. 


  1. What behavioural deficits were observed?

    1. Decreased correct response, increased reference error, impaired spatial and configural memory (can test), increased latency to escape (Barnes Maze), impaired memory retrieval, reduced integrated cognitive z-score

Importantly, locomotor activity remained unchanged, indicating that the deficits were cognitive, rather than motivational or motor-related.


  1. How did CBD affect spatial memory?

    1. CBD administered during adolescence: Increased correct response, reduced reference errors, reduced latency in Barnes Maze, improved reversal learning, restored integrated cognitive z-scores.

CBD improved memory performance specifically, without affecting locomotion, suggesting a targeted cognitive rescue effect.


  1. What is the role of NR1 and NR2A?

    1. Both subunits of the NMDA receptor (NMDAR), critical for synaptic plasticity. NR1 is required for receptor formation and stability. NR2A influences plasticity direction and synaptic refinemement.

In this study, Prenatal THC increased NR1 (possible overactivation) and decreased NR2A (impaired synaptic maturation). 

This imbalance likely contributed to disrupted hippocampal plasticity and memory deficits. 


  1. Why is adolescence considered a “window of opportunity”?

    1. Adolescence is a period of ongoing synaptic refinement, active hippocampal plasticity, and continued maturation of the excitatory-inhibitory balance. 

Because the brain is still plastic, interventions during this time (like CBD) may partially reprogram altered neural circuits, making it a critical therapeutic window.


  1. Did CBD restore all molecular abnormalities?

    1. No, CBD reduced NR1, mGluR5, Homer 1, and CB1R, but did not fully restore NR2A, PSD95, or normalize HINT1



Essay Questions:

  1. Discuss how prenatal THC exposure alters hippocampal plasticity and memory.

    1. Prenatal THC exposure during gestational days 5-20 disrupts hippocampal development, leading to long-lasting memory deficits in adolescent rats. Moleculary, THC increases NR1, mGlueR5, Homer 1, CB1R, and HINT1 while decreasing NR2A and PSD95, reflecting excitatory/inhibitory imbalance and impaired synaptic plasticity. Behaviourally, affected rats show fewer correct responses, more reference errors, increased latency in spacial tasks, and reduced integrated cognitive z-score, indicating deficits in spatial and configural memory. Mechanistically, overactivation of fetal CB1 receptors alters glutamatergic signaling and disrupts hippocampal circuitry, impairing the ability to form and retrieve memories. Overall, prenatal THC leads to both molecular and behavioural alterations that compromise hippocampal plasticity and cognitive function.


  1. Evaluate CBD as a potential therapeutic interve

    1. CBD administered during adolescence can partially rescue the cognitive deficits caused by prenatal THC exposure. Behaviorally, CBD improves correct responses, reduces reference errors, decreases latency in the Barnes Maze, and restores integrated cognitive z-scores without affecting locomotor activity, suggesting a targeted effect on memory. Molecularly, CBD reduces overexpressed NR1, mGluR5, Homer 1, and CB1R, partially normalizing excitatory signaling, though NR2A, PSD95, and HINT1 remain abnormal. These findings indicate that adolescence is a critical window of plasticity during which CBD can fine-tune synaptic function and improve memory. While the rescue is partial and limited to one dose and one sex, the study supports CBD as a promising therapeutic intervention for mitigating prenatal cannabis-induced hippocampal dysfunction. 

  2. Compare behavioural and molecular effects of prenatal THC exposure.

    1. Prenatal THC exposure affects both behaviour and molecular signaling in adolescent rats. Behaviourally, rats display impaired spatial and configural memory, characterized by fewer correct responses, more reference errors, and increased latency in aversive tasks like the Barnes Maze. Molecularly, prenatal THC exposure disrupts hippocampal plasticity by increasing NR1,mGluR5, Homer 1, CB1R, and HINT1 while decreasing NR2A and PSD95, reflecting excitatory/inhibitory imbalance and synaptic instability. These molecular changes provide a mechanistic explanation for the behavioural deficits, showing how altered glutamatergic and endocannabinoid signaling translates into impaired learning and memory. The parallel between behavioural impairment and synaptic disruption illustrates the tight coupling between hippocampal plasticity and cognitive function. 


  1. Explain how excitatory/inhibitory imbalance contributes to cognitive deficits.

    1. Cognitive deficits from prenatal THC exposure result largely from an imbalance between excitatory and inhibitory signaling in the hippocampus. Overactivation of CB1 receptors increases NR1, mGluR5, Homer 1, and HINT1 while decreasing NR2A and PSD95, enhancing excitatory signaling while reducing the stability of synapaptic connections. This imbalance disrupts long-term potentiation (LTP) and long-term depression (LTD), which are essential for learning and memory. As a result, hippocampal circuits cannot properly encode, store, or retrieve spatial configural information, leading to behavioural deficits such as fewer correct responses and increased reference errors. Restoring excitatory/inhibitory balance, can partially rescue these deficits by normalizing synaptic signaling and plasticity.