Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Dopamine neuron development is crucial for motivated behaviors and implicated in psychopathologies.
• Sonic Hedgehog (Shh) signaling is a known morphogen for midbrain dopamine neurons.
• Specific roles of Shh signaling in the ventral tegmental area (VTA) are emerging.

Purpose of the Study:

• To investigate the role of the Shh receptor Cdon in the development of VTA and substantia nigra pars compacta (SNc) dopamine neurons.
• To determine how Cdon deficiency affects dopamine neuron number and connectivity.
• To assess the behavioral consequences of altered dopamine signaling in Cdon-deficient mice.

Main Methods:

• Analysis of Cdon expression in embryonic ventral midbrain progenitor zones.
• Quantification of tyrosine hydroxylase (TH)-positive neurons in VTA and SNc of Cdon(-/-) and wild-type mice.
• Assessment of dopamine presynaptic sites and dopamine levels in the medial prefrontal cortex (mPFC) of adult mice.
• Behavioral testing of amphetamine-induced plasticity in adult Cdon(-/-) mice.

Main Results:

• Cdon is expressed in the embryonic ventral midbrain progenitor zone, and its absence increases proliferating cells.
• Cdon deficiency leads to a significant increase in TH-positive neurons in the VTA, persisting from birth into adulthood.
• The number of TH-positive neurons in the SNc remains unaffected by Cdon deficiency.
• Adult Cdon(-/-) mice exhibit increased dopamine presynaptic sites and dopamine levels in the mPFC.
• Cdon(-/-) mice display impaired behavioral plasticity in response to repeated amphetamine treatment.

Conclusions:

• Cdon plays a critical role in regulating the development and diversity of midbrain dopamine neurons.
• Cdon deficiency specifically impacts the development of the mesocortical dopamine pathway originating from the VTA.
• Altered dopamine signaling in the mPFC due to Cdon loss affects behavioral plasticity.