Effects Of Serotonin Transporter Knockout On Thestructure And Function Of The Auditory Cortex

Selective serotonin reuptake inhibitors(SSRIs)can exhibit auditory dysfunction and abnormal side effects during antidepressant therapy.However,the neurological and pharmacological mechanisms that cause this adverse reaction are unclear.SSRIs can significantly affect the activity of serotoninergic neurons in the central nervous system.The serotonin transporter(SERT)plays a modulate role in neuronal activity of serotoninergic neurons.Therefore,SERT is also considered to be a potential target for the antidepressant drugs.To investigate the role of SERT in auditory dysfunction which caused by SSRI drugs,we investigated the effects of SERT on the structure and function of the auditory cortex.First,we found that the SSRIs drug citalopram(CTM)can trigger anxiety-like behavior in mice.We further examined the effects of CTM on auditory mismatch negativity(MMN)function in mice,and the results showed that CTM treatment significantly affected the MMN function in mice.It is suggested that the SSRIs drug CTM can cause similar mental and auditory adverse events in mice compared with clinical patients.To clarify the role of SERT in auditory dysfunction and the abnormalities caused by SSRI drugs,we examined the effects of SERT KO on anxiety-like behavior and sensorimotor gating in SERT KO mice.It was found that SERT KO mice exhibited typical anxiety-like behavior in elevated-plus maze,open field test and light-dark box test.In the prepulse inhibition(PPI)experiment,the amplitude of auditory startle reflex in SERT KO mice was significantly reduced compared to wild-type mice.The auditory event-related potential(ERP)recorded on the auditory cortex of SERT KO mice showed no significant difference in P1,N1 and P2 waves representing auditory responses compared with WT.However,the magnitude of the mismatch negativity(MMN)detected with the oddball paradigm was significantly reduced in SERT KO mice.The results above suggest that both CTM treatment and SERT KO can cause obstacles on sound frequency discrimination and acoustic information processing in the auditory cortex.To determine the possible reason of auditory cortical dysfunction which caused by SERT KO,we examined the structure and function of the auditory cortex in SERT KO mice.Golgi-Cox staining showed that the dendritic length of the fifth layer(LV)pyramidal neurons and the second-third layer(L?-?)interneurons in the auditory cortex of the SERT KO mice was significantly shortened,and the the number and density of dendritic spines were significantly reduced.Functionally,the frequency tonotopic maps of the AI region of the SERT KO mouse was disordered,indicating that the SERT KO caused disturbances in the auditory cortex to the sound frequency.Our recording of the acoustic response of a single neuron in the AI region showed that the threshold of the SERT KO mouse AI neurons was significantly higher than that of the WT,and the frequency-intensity tuning curve for the acoustic stimulation response was significantly broadened.These functional changes,combined with morphological results,suggest that SERT KO can cause auditory abnormalities similar to those of SSRIs treatment in mice.The effect of decreased SERT function on the morphological structure and function of the auditory cortex may be a possible reasons of adverse events such as the auditory dysfunction and abnormalities which caused by SSRIs.