CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses.

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Presynaptic active zones (AZs) are critical for neurotransmission, but transsynaptic signal organization remains unclear.
• CASKIN1 and CASKIN2 are scaffold proteins potentially involved in presynaptic assembly and LAR receptor protein tyrosine phosphatase (LAR-RPTP) interactions.

Purpose of the Study:

• To investigate the roles of CASKIN1 and CASKIN2 in synaptic transmission, AZ organization, and N-methyl-D-aspartate receptor (NMDAR) function.
• To elucidate the molecular mechanisms underlying CASKIN2's function, including its interaction with PTPσ.

Main Methods:

• Conditional knockout (cKO) mouse models deficient in CASKIN1 and/or CASKIN2.
• Electrophysiological recordings of synaptic transmission and long-term potentiation.
• Analysis of AZ protein arrangement and NMDAR surface expression.
• Biochemical assays to study CASKIN2 dephosphorylation and multimerization.

Main Results:

• CASKIN2, not CASKIN1, is essential for synaptic transmission, strength, and AZ organization in glutamatergic synapses.
• Presynaptic CASKIN2 regulates postsynaptic NMDAR responses, surface expression, and long-term potentiation in CA1 pyramidal neurons.
• PTPσ-mediated regulation of CASKIN2 is critical for synaptic function, NMDAR activity, and F-actin rearrangement.
• CASKIN2 and PTPσ are involved in novel object location memory.

Conclusions:

• CASKIN2 plays a critical role in regulating excitatory synaptic transmission and NMDAR-mediated functions.
• CASKIN2 orchestrates LAR-RPTP-mediated transsynaptic signaling pathways essential for synaptic plasticity and memory.
• PTPσ-dependent modulation of CASKIN2 is a key mechanism for synaptic function.